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Investigational use for primary Raynaud's phenomenon; mechanism via local vasodilation and rheologic improvement. No RCT evidence.

Investigational use for primary livedo reticularis; very limited evidence. Secondary causes (lupus, APLAS) require rheumatology referral.

Investigational use to soften and remodel insulin injection-related lipohypertrophy nodules; very limited evidence.

Investigational use for stable-phase Peyronie's disease; case-report-level evidence only. Standard treatments (verapamil, collagenase, surgery) remain first-line.

Investigational adjunctive use for Ménière's disease; very limited evidence. Standard management (diet, betahistine, intratympanic therapy) remains primary.

Investigational adjunct for peripheral vertigo persisting after Epley maneuvers or during prolonged vestibular neuritis recovery; anecdotal.

Investigational use for posterior tibial nerve entrapment at the medial ankle; very limited case-report evidence.

Investigational use for non-pregnancy-related pubic symphysis dysfunction including athletic osteitis pubis; anecdotal evidence.

Highly investigational use for episodic cluster headache between attack cycles; very limited anecdotal data, not for active attacks.

Highly investigational use for severe nodulocystic acne refractory to isotretinoin; very limited anecdotal evidence and significant scarring risk concerns.

Investigational use for localized cutaneous lichen planus refractory to topical corticosteroid; very limited case-report evidence.

Investigational adjunct for chronic anal fissure refractory to medical therapy; very limited case-report evidence; surgical sphincterotomy remains gold standard.

Enzyme that degrades hyaluronic acid in extracellular matrix — 'spreading factor' enhancing diffusion of other SGS compounds.

Platelet GP IIb/IIIa antagonist family member — RGD-motif containing.

Plasma kallikrein-kinin system modulator — anti-inflammatory pathway distinct from cyclooxygenase.

Modulates host NOS activity at bite site — contributes to vasodilation phase of feeding.

Histamine-receptor-acting compound — contributes to local vasodilation at feeding site.

Cholinergic vasodilator contributing to feeding-site vascular dilation.

ECM-degrading enzyme — facilitates spread of salivary compounds at the bite site.

ADP-degrading enzyme — prevents platelet aggregation by hydrolyzing ADP at bite site.

Inhibitor of tissue factor / Factor VIIa complex — blocks extrinsic coagulation pathway.

Modulates the thrombin-thrombomodulin axis — implications for protein C pathway.

Vascular endothelial growth factor pathway modulator — angiogenic and wound-healing implications.

Platelet-derived growth factor pathway modulator — implications for wound-healing.

Modulates prostaglandin and leukotriene cascades — anti-inflammatory pathway.

Direct thrombin inhibitor from the Asian buffalo leech — hirudin homolog described in Hirudinaria manillensis secretome.

Anticoagulant peptide described in the terrestrial Asian leech Haemadipsa zeylanica.

Direct thrombin inhibitor homolog cataloged in the Chinese medicinal leech Whitmania pigra secretome.

Small direct thrombin inhibitor described in the fish leech Piscicola geometra secretome.

Anticoagulant peptide described in the North American medicinal leech Macrobdella decora.

Second isoform of destabilase — lysozyme / isopeptidase activity targeting cross-linked fibrin.

Alternate fibrin-cleaving enzyme reported in Hirudo medicinalis salivary secretions.

Dual-function protease degrading both fibrin clot scaffolds and collagen extracellular matrix.

Salivary factor reported to modulate the bradykinin / kinin-kallikrein vasoactive cascade.

Salivary factor reported to modulate the substance P / neurokinin-1 nociceptive pathway.

Granulin-family peptide identified in Hirudo medicinalis — putative growth-factor / wound-healing analog (mechanistic only).

Putative neuroactive signaling peptide identified in leech salivary tissue — named by analogy to mollusc buccalin; function speculative.

Substrate-mimetic peptide segment identified in leech salivary transcriptome — putative thrombin substrate / competitive inhibitor variant.

Carbohydrate-binding lectin reported in Hirudo medicinalis salivary glands — putative agglutinin / immune modulator.

Saposin-like lipid-binding peptide identified in leech salivary transcriptome — putative membrane-active component.

Thrombospondin-type repeat (TSR)-domain protein identified in leech salivary transcriptome — putative platelet / matrix interactor.

Putative PLA2 inhibitor identified in leech salivary transcriptome — candidate eicosanoid-cascade modulator.

C-type lectin domain protein identified in Hirudo medicinalis salivary transcriptome — putative carbohydrate / glycoprotein binder.

Whitmania pigra salivary anticoagulant gene family (Huang 2026 transcriptome) — seven coagulation-related transcripts including fibrinolytic enzymes, neutrophil-elastase inhibitors, factor Xa inhibitors.

Hirudin-paralog family lacking some structural hirudin features — Müller 2016 phylogenetic characterization across Hirudo and Hirudinaria genera.

Putative progranulin gene with 122 cysteine residues and nine tandem repeats — distinctive structural organization (Lin 2025 chromosome-level genome).

Lineage-specific 8.7-25-fold expansion of bdellin protease-inhibitor gene family in H. yanyuanensis genome (Lin 2025) — candidate driver of terrestrial-blood-feeding adaptation.

Lineage-specific expansion of LDTI (leech-derived tryptase inhibitor) gene family in H. yanyuanensis (Lin 2025) — candidate mast-cell modulator repertoire.

Three macin antimicrobial peptide paralogs from Asian buffalo leech — Yu 2025 documents Hman1 functional, Hman2 / Hman3 partly pseudogenized.

Chromosome-level genome of H. bpling (Khan 2025) annotates 20+ anticoagulant gene families including 'Bplins' — a novel species-specific factor family.

Novel anticoagulant factor identified in the Hirudo nipponia salivary-gland transcriptome — Kim 2024 de novo assembly + in situ hybridisation.

Novel ghilanten family anticoagulant in the Hirudo nipponia salivary-gland transcriptome — Kim 2024 spatial expression mapping.

Novel bdellin family Kazal-domain trypsin / plasmin inhibitor identified in the Hirudo nipponia salivary-gland transcriptome — Kim 2024.

Previously unrecognized immune-related glioma-pathogenesis-related protein 1 homolog in the Hirudo nipponia salivary gland — Kim 2024.

181 differentially expressed proteins (72 up / 109 down) in starved Hirudo nipponia salivary glands — Cai 2024 proteomic + transcriptomic profiling.

8.7–25× lineage-specific expansion of the bdellin gene family in the terrestrial blood-feeding leech Haemadipsa yanyuanensis — Lin 2025 chromosome-level genome.

Lineage-specific expansion of the leech carboxypeptidase inhibitor (LCI) family in the terrestrial blood-feeding leech Haemadipsa yanyuanensis — Lin 2025.

Distinctive progranulin paralog with 122 cysteine residues + nine tandem repeats in the terrestrial blood-feeding leech Haemadipsa yanyuanensis — Lin 2025.

First chromosome-level Hirudo verbana genome (14 pseudomolecules, 0.18 Gb, ERGA-BGE 2026) framing the southern medicinal leech as a primary genomic reference.

Chromosome-level W. pigra genome unexpectedly carries 79 antithrombotic genes — more than the 72 in blood-sucking H. manillensis (Liu 2024).

Expanded FBN1 (fibrillin-1) + GLB3 (globin-3) gene families across H. nipponia / H. manillensis vs W. pigra — Zheng 2023 functional-genomic comparison.

Structural determinants (Gln192, Lys218) explaining why eglin C, a classical broad-spectrum chymotrypsin / elastase inhibitor, poorly inhibits human chymotrypsin-like protease — Németh 2024.