22 HHT & Other Bleeding Disorders

Key Points

HHT (Osler-Weber-Rendu): AD, dysregulated angiogenesis; 2nd most common inherited bleeding disorder (1:5000)
Genetics: ENG (55%), ACVRL1/ALK1 (35%), SMAD4 (rare)—TGF-β pathway defects
Manifestations: Epistaxis >90% by age 40; telangiectasia 95% by 4th decade; GI bleed 30-40%; pulm AVM 30-50%; cerebral AVM 5-18%; hepatic 75%
Curacao criteria: 3 of 4 = definite (epistaxis, telangiectasia, visceral AVM, FHx in 1° relative)
Management: Iron repletion, topical tx; bevacizumab/thalidomide ± emicizumab; endovascular embolization for pulm/cerebral AVM
Acquired hemophilia A (AHA): Anti-FVIII antibodies; treat w/ emicizumab or APCC/rFVIIa + immunosuppression
Rare factor deficiencies: Replace factor concentration; fibrinolytic disorders use TXA/EACA

22.1 HHT: Genetics & Manifestations

TGF-β pathway mutations → loss of endothelial stability
- ENG (chr 9q34): 55% of cases
- ACVRL1 (chr 12q13): 35%
- SMAD4 (chr 18q21): rare, polyposis overlap
- BMPR2, GDF2, RASA1: small %
Pathophysiology: Defective capillary → direct AV shunting & hemorrhage
AD inheritance: ~95% penetrance; homozygous lethal

Epistaxis: >90% by age 40; recurrent, spontaneous ± severe; life-threatening in some
Telangiectasia: 95% by 4th decade; lips, oral mucosa, fingers, palms, nail beds
GI bleeding: 30-40%; 80% from upper GI; progressive, recurrent
Cerebral AVM: 5-18% lifetime; 4% hemorrhage/yr; screen w/ MRI at diagnosis
Pulmonary AVM: 30-50% lifetime; risk of paradoxical stroke via R→L shunt; orthostatic dyspnea, hemoptysis; screen w/ echo or CT
Hepatic AVM: 75%; mostly ⊗Sx; if Sx → high-output HF, portal HTN, hepatic necrosis
Other: Mucosal bleed, IDA, iron deficiency w/o anemia

Curacao criteria: 3 of 4 = definite HHT
- Spontaneous, recurrent epistaxis
- Cutaneous/mucosal telangiectasia
- Visceral involvement (GI bleed, pulm/cerebral/hepatic AVM)
- FHx in 1° relative
- (5th: genetic mutation ENG, ACVRL1, SMAD4)
Genetic testing: Confirm diagnosis; cascade testing in relatives
AVM screening at diagnosis:
- Brain: MRI ± contrast (5-18% prevalence)
- Pulm: Transthoracic contrast echo or CT (30-50%)
- Hepatic: Consider if Sx or ↑ LFTs

Iron repletion (foundation): IV iron preferred (↓ malabsorption, ↑ tolerability)
Topical: Thrombin, TXA, estrogen, cautery
Systemic antifibrinolytic: TXA for mild-moderate bleed
Antiangiogenic agents:
- Bevacizumab (anti-VEGF): IV or intranasal
- Thalidomide (TNF-α inhibitor): oral
- Emicizumab (FVIII-FIX bridge): 1.2 mg/kg SC weekly (w/ lead-in); ↓ epistaxis & transfusion
Acute bleed: Cryo (fibrinogen, FVIII), FFP, PCC

Pulm AVM: Endovascular embolization (standard); surgery if not amenable
- Goal: ↓ paradoxical stroke risk via R→L shunt
Cerebral AVM: Treat if high rupture risk
- Options: Endovascular embolization, resection, stereotactic radiosurgery
Hepatic AVM: Intervene only if Sx (high-output HF, portal HTN, encephalopathy)
- Consider liver Tx if decompensated

Definition: Anti-FVIII antibodies (autoimmune); acquired (not congenital)
Epidemiology: 1.4/million/yr; age ~60; slight female ↑
Etiologies: ~50% assoc. w/ pregnancy, malignancy, autoimmune disease, meds; 50% idiopathic

Bleeding: Sudden onset (unlike congenital); cutaneous, mucosal, soft tissue, ICH
Lab findings:
- Prolonged aPTT (does NOT correct w/ normal plasma) → indicates inhibitor
- FVIII activity (OSA or CSA); Bethesda assay quantifies inhibitor titer
- Low-responder: <20 BU/mL; high-responder: >20 BU/mL

Acute hemostasis:
- Emicizumab (FVIII-FIX bridge): 1.2 mg/kg SC weekly (preferred)
- Bypassing agents:
  - APCC/FEIBA: 50-100 IU/kg IV (preferred over rFVIIa)
  - rFVIIa: 90 μg/kg IV
Immunosuppression (long-term):
- Prednisone (1st-line): 1 mg/kg daily, taper per inhibitor response
- Cyclophosphamide: Add if steroid-resistant
- Azathioprine, rituximab: Limited data
Response: ~60-80% achieve inhibitor eradication
Inhibitor management:
- Low-responders: high-dose FVIII
- ITI protocol: repeated FVIII (variable efficacy; better in congenital); emicizumab now standard

Genetic (FII, V, VII, X, XI, XII): Homozygous/compound het; prevalence 1:500K-1M per factor
Acquired: Inhibitors, consumption (cancer, sepsis), malabsorption (vitamin K, liver disease)
Presentation: Variable; ⊗Sx to spontaneous bleed
Diagnosis: Factor activity assay, aPTT mix, PT, direct assay
Treatment: Factor replacement w/ PCC or factor concentrate (high-purity preferred to ↓ thrombotic risk)

Congenital: α2-antiplasmin deficiency, PAI-1 deficiency, plasmin deficiency, dysfibrinogenemia
Acquired: Liver disease, malignancy (esp. AML), DIC, massive transfusion, post-op bleed
Labs: ↑ FDP, ↑ D-dimer, ↓ fibrinogen; abnormal euglobulin lysis or TEG
Treatment: Antifibrinolytic agents
- TXA: 15-25 mg/kg IV or oral TID
- EACA: 100-150 mg/kg load, then 25-50 mg/kg q4-6h
- Caution: Monitor thrombotic risk; avoid w/ bypassing agents in hemophilia

Gene therapy (AAV vectors):
- FDA approved for hemophilia A & B
- Phase 2-3: sustained ↑ FVIII/FIX; on-demand → prophylaxis conversion
- Durable ↓ bleed rates, factor use; ↑ QOL
Angiogenesis inhibitors for HHT:
- Bevacizumab (anti-VEGF): ↓ epistaxis, transfusion
- Thalidomide (TNF-α inhibitor): variable efficacy
- Emicizumab: off-label for rare factor deficiencies w/ inhibitors
Emerging: mAb to VEGF/TGF-β/Notch; small-mol angiogenesis inhibitors; concizumab (FXI inhibitor)

Clinical Pearls

HHT: Suspect w/ recurrent epistaxis + telangiectasia + FHx; screen brain & pulm AVM at diagnosis (paradoxical stroke risk); iron + topical → bevacizumab/thalidomide/emicizumab if refractory
AHA: Distinguish from congenital (acquired, normal baseline); acute: APCC/rFVIIa; prophylaxis: emicizumab; long-term: prednisone ± CYC for inhibitor eradication; monitor titers
Rare factors & hyperfibrinolysis: High suspicion for isolated PT/aPTT prolongation; replace factor or use TXA/EACA; multidisciplinary consult for complexity & thrombotic risk