3  Women’s Health Issues in Hematology

Key Points
  • VTE: 3-10× ↑ risk in pregnancy/postpartum; LMWH preferred; avoid warfarin (teratogenic) & DOACs
  • Thrombocytopenia in pregnancy: ITP vs gestational; vary Tx by etiology (ITP vs HELLP)
  • Anemia: Evaluation same as nonpregnant; physiologic plasma volume ↑ dilutes Hgb
  • HMB: 80-90% w/ bleeding disorder; 70% on anticoagulation report HMB
  • CHCs: ↑ arterial & venous thrombosis; counsel high-risk women; transdermal safer
  • APS + prior loss: LMWH & low-dose aspirin per 2023 ACS/EULAR
  • Transgender men: Testosterone ↑ VTE risk; monitor closely

3.1 Hematologic Health in Women: Multidisciplinary Approach

  • Hematologists, OB-GYNs, MFM specialists, transfusionists coordinate care
  • SCD, inherited bleeding disorders, thrombosis need specialized labs

3.2 Hematologic Issues in Pregnancy

3.2.1 Venous Thromboembolism & Thrombophilia

VTE risk: 3-10× ↑ vs nonpregnant - Incidence: 1 per 1000 pregnancies - Peak: Antepartum & early postpartum (first 2 weeks) - Postpartum ~2× antepartum risk

Pathophysiology of hypercoagulability: - ↑ Procoagulants: Factor V, VIII, X, fibrinogen, vWF - ↓ Anticoagulants: Protein S, ↑ APC resistance - ↓ Fibrinolysis: ↓ tPA, ↑ PAI-1 - Venous stasis: Gravid uterus compression, iliac vein obstruction - Vascular injury: Placental implantation, cesarean delivery

Inherited thrombophilia: - Accounts for ~50% VTE in pregnancy/postpartum - Common: FV Leiden, FII G20210A, Protein C/S deficiency, AT deficiency

Diagnosis: DVT: - 1st line: Compression U/S (whole-leg; pelvic if high suspicion) - D-dimer unreliable in pregnancy (normally ↑, esp 2nd/3rd trim) - Serial U/S if high suspicion & negative; consider MRI pelvic DVT - POCUS emerging; YEARS criteria w/ U/S + D-dimer useful

Diagnosis: PE: - V/Q scan safe; fetal dose below threshold - CTPA acceptable if high clinical suspicion

VTE Risk Stratification in Pregnancy
Risk Category Antepartum Postpartum
Common ↑ BMI, immobility, prior VTE, superficial thrombophlebitis, family Hx Infection, cesarean, hematoma, preeclampsia, transfusion

3.2.2 Anticoagulation in Pregnancy & Postpartum

LMWH (preferred agent) - Does NOT cross placenta; safe fetus - vs UFH: ↓ bleeding, predictable response, ↓ HIT, ↓ bone loss - Dosing: BID (more convenient) - AE: Antepartum bleed 0.5-1.5%; postpartum 1-2%; skin 2-3%; osteoporosis rare - UFH causes 2% vertebral fractures; LMWH does not

Warfarin (contraindicated) - Teratogenic weeks 6-12: Nasal hypoplasia, stippled epiphyses, limb hypoplasia - Risk: 4-10% embryopathy; also CNS (optic atrophy), neurodevelopmental delays - Fetal hemorrhage, fetal loss

DOACs (contraindicated) - Cross placenta; unknown fetal hemorrhage risk - Cross breast milk; contraindicated breastfeeding

Alternatives: - Fondaparinux: HIT-safe, QD dosing; placental crossing unclear - Danaparoid: HIT-safe, doesn’t cross placenta; not available US - UFH: No cross placenta; ↑ bone loss, HIT risk

Anticoagulants in Pregnancy
Agent Key Features
LMWH BID, ↓ HIT, ↓ bone loss; injection
UFH ↑ Bone loss; HIT risk; IV/SC
Warfarin 4-10% embryopathy; teratogenic
DOAC Crosses placenta & breast milk
Fondaparinux QD, HIT-safe; placental crossing unclear

VTE Prevention (2023 ASH): - Prior unprovoked/hormonal VTE: Antepartum prophylaxis + 6 wk postpartum - Prior VTE w/ major provoked risk: 6 wk postpartum only - High-risk thrombophilia (homozygous FV, compound heterozygosity, AT deficiency): Antepartum + postpartum - Mild heterozygous (FV, FII): No prophylaxis unless strong family Hx - Protein C/S deficiency: Postpartum YES if family Hx - ART w/ OHSS: Antepartum prophylaxis recommended

3.2.3 Superficial Vein Thrombosis (SVT) in Pregnancy

  • Tx: LMWH 10 days–2 weeks
  • Duration: Severity, proximity saphenofemoral junction, other VTE risk
  • Adjuncts: Warm/cool compresses, compression stockings
  • NSAIDs: Contraindicated in pregnancy

3.2.4 Ovarian Vein Thrombosis (OVT)

  • Incidence: 1 per 600–2000 pregnancies; 30% vaginal, 46% cesarean delivery
  • Timeline: Postpartum; fever, lower abdominal pain
  • Often asymptomatic: Likely benign; data limited
  • Complications: Sepsis, IVC thrombosis (25-30%), PE
  • Symptomatic/extensive: Anticoagulation ~3 months

3.2.5 Inherited Thrombophilia & Placenta-Mediated Complications

  • FV Leiden alone: Modest pregnancy loss association; NOT independent LMWH indication
  • LMWH + recurrent loss + inherited thrombophilia: NO benefit (TIPS trial)
  • Meta-analysis: LMWH does NOT ↑ live births in recurrent loss
  • AE: 45% report injection site reactions; no ↑ major bleeding
Clinical Pearl: Antiphospholipid Syndrome (APS)
  • APS + prior loss: LMWH & low-dose aspirin (2023 ACS/EULAR)
  • APS + prior thrombosis: Requires anticoagulation; weigh thrombotic vs pregnancy benefit
  • Diagnosis: Lupus anticoagulant, anticardiolipin, anti-β2GPI (≥2 tests ≥12 wk apart)

3.2.6 Assisted Reproductive Technology (ART)

  • VTE risk: 4-5× ↑ in pregnancy post-IVF vs spontaneous conception
    • Peak: 1st trimester, ~1 wk after embryo transfer
  • OHSS (1-5% cycles): Human chorionic gonadotropin triggered
    • ↑ Capillary permeability, hemoconcentration, hypovolemia
    • Severe OHSS → arterial events in 90% (median 11 d post-transfer)
    • Prophylaxis if high-risk thrombophilia or prior VTE

3.2.7 Mechanical Heart Valves in Pregnancy

  • Challenge: High arterial thromboembolism risk w/o anticoagulation
  • Warfarin: ↓ Effective (INR 2.5-3.5) but highest fetal risk
  • Alternative: UFH + therapeutic LMWH sequential
    • Subtherapeutic LMWH (lack anti-Xa monitoring, poor adherence) may cause events
  • Team: Involve cardiology; ESC 2018 & ACC/AHA 2020 available

3.2.8 Thrombocytopenia in Pregnancy

Prevalence: 5-10% pregnancies; 80% asymptomatic

Differential diagnosis: - Gestational (75%): Mild, resolves 1-8 wk postpartum, recurs - ITP (1 per 2000): 1st trimester, >30,000/μL may need Tx - Preeclampsia: 5-8% pregnancies; 50% develop thrombocytopenia - HELLP: 0.1-1% pregnancies; MAHA + ↑ LDH/AST + <100,000/μL - TMA (TTP, HUS): ADAMTS13 <10%; microangiopathic hemolysis - DIC: ↓ Fibrinogen, ↑ PT/PTT, schistocytes

Management: - Asymptomatic + >70,000/μL: Observe (2021 SOAP) - Symptomatic or <30,000/μL: IVIG, corticosteroids, transfusion - Delivery threshold: >50,000/μL vaginal, >100,000/μL epidural typical

Preeclampsia/Eclampsia: - MAHA; normal PT/PTT; ↑ LDH; microspherocytes - Cure: Delivery ≥37 wk if severe or any end-organ damage - Magnesium sulfate for seizure prophylaxis

HELLP Syndrome: - Diagnostic triad: MAHA (schistocytes, ↓ Hgb, ↑ LDH) + ↑ LFTs (>2× ULN) + <100,000/μL platelets - Presentation: RUQ/epigastric pain (50%), nausea/vomiting - vs TTP: Normal PT/PTT; ADAMTS13 normal/near-normal (vs <10% TTP) - Urgent delivery required; high maternal morbidity

3.3 Hematologic Issues in Nonpregnant Women

3.3.1 Heavy Menstrual Bleeding (HMB) in Premenopausal Women

Definition & detection: - >80 mL blood per cycle (gold standard) - Pictorial Blood Assessment Chart (PBAC): Score >100 = abnormal - Clinical: Clots >1 cm, hourly pad/tampon changes (flooding)

Prevalence of bleeding disorder: - 80-90% HMB have underlying bleeding disorder (especially vWD, factor deficiency) - vWD most common: 90% of HMB diagnosed w/ bleeding disorder

Screening tool (Philips): - 8 questions: HMB severity, family Hx, excess bleeding history, anemia Tx - Sensitivity: 89% (↑ 93% w/ ferritin ≤20 ng/mL) - PFA-100 abnormal ↑ vWD sensitivity to 92%

Laboratory workup: - CBC (Hgb, ferritin) - PT/PTT, fibrinogen - vWF activity & antigen, factor VIII - Platelet aggregation if labs normal - Timing: Don’t delay for menses; stop hormonal therapy before labs

HMB on anticoagulation: - ~70% report HMB on anticoagulation - Risk-benefit discussion required; consider hemostatic agents

Clinical Pearl: HMB Management
  • Severity & fertility goals guide Tx approach
  • Want fertility: Hemostatic agents (tranexamic acid, DDAVP, factor replacement)
  • Completed childbearing: Hormonal or surgical (ablation, hysterectomy)

Hormonal treatment: - CHCs/progestin-only: ↓ Flow, regulate cycle - Transdermal estrogen: Consider if VTE risk - Levonorgestrel IUD: Effective, ↓ systemic absorption

Hemostatic therapy (specific & nonspecific): - Tranexamic acid (TA): Antifibrinolytic; PBAC ↓ ~105 points - No ↑ VTE per studies (caveat: excluded anticoagulated, thrombotic Hx) - DDAVP: Type 1 vWD, mild factor VIII deficiency - 300 μg intranasal days 1-3 cycle - PBAC improvement ~64 points (less effective than TA) - Aminocaproic acid: Alternative antifibrinolytic - Factor replacement: Specific for factor deficiency - Transfusion: Severe anemia, ongoing bleeding

Surgical management (completed childbearing): - D&C: Temporary only; may worsen bleeding - Endometrial ablation: Highly effective; 8.5% need repeat - Uterine artery embolization: Effective for fibroids - Hysterectomy: Definitive; ↑ QOL vs medical Tx

3.3.2 Thrombosis & Exogenous Hormones

Combined Hormonal Contraceptives (CHCs): - Risk: 2-3× ↑ VTE; 1.5-3× ↑ arterial thrombosis - Absolute VTE: 10-60 per 100,000 woman-years (vs 20-40 baseline) - Mechanism: ↑ Factor VIII, vWF, fibrinogen; ↓ protein S, ↑ APC resistance

Estrogen dose & formulation: - High risk: Ethinylestradiol 50 μg - Intermediate: Ethinylestradiol 30-35 μg - Lower-intermediate: Ethinylestradiol 20 μg - Very low: Transdermal > conjugated equine estrogen

Progestin contribution: - Desogestrel, drospirenone, cyproterone acetate may ↑ VTE further - Progestin-only: No ↑ VTE risk

High-risk groups for thrombosis: - Smoking, esp age >35 - Migraine w/ aura (stroke risk) - Prior VTE/thrombosis - Thrombophilia (FV Leiden, FII, APS) - Immobility (major surgery, long flights)

VTE/Arterial Risk w/ CHC Use
Risk Factor Venous Arterial
Smoking 8-50× Modest
Migraine w/ aura 7-50× Unknown
Lupus anticoagulant 3-8× 3-8×
SLE/RA 3-8× / 2-2.5× 3-8× / 1.3-2.5×
IBD 3-4× 1-2×
Nephrotic syndrome 3-10× 3-10×

Counseling for thrombotic history: - Avoid CHCs; use progestin-only (pill, implant, IUD) or non-hormonal - If on long-term anticoagulation: Avoid CHC or ensure anticoagulation

Menopausal Hormone Therapy (HT): - Goals: Vasomotor (hot flashes), genitourinary (vaginal atrophy), bone loss - Risk w/ thrombotic Hx: ↑ VTE; weigh symptom benefit - Safer options: Transdermal estrogen, vaginal estrogen, non-hormonal - See Chapter 7 for detailed management

Mechanisms of estrogen-mediated thrombosis: - ↑ Factor VIII, vWF, fibrinogen - ↓ Fibrinolytic activity, protein S - APC resistance develops

3.3.3 Female-to-Male Hormone Therapy (Transgender Men)

  • Testosterone standard transition hormone
  • ↑ RBC mass: Expected physiologic response
  • ↑ VTE risk: Observed; monitor closely
  • Counseling: Assess VTE risk before starting; regular surveillance

3.4 Bibliography