Spontaneous Resolution of SDH and Coagulopathy in Trauma Patients: Theories and Mechanisms

from reportlab.lib.pagesizes import A4
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm
from reportlab.lib import colors
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import ListFlowable, ListItem

OUTPUT = "/tmp/workspace/sdh-coagulopathy-pdf/SDH_Coagulopathy_Spontaneous_Resolution.pdf"

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    title="Spontaneous Resolution of SDH and Coagulopathy in Trauma",
    author="Orris Medical Reference",
)

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story = []

# ═══════════════════════════════════════════════════════════════════════════════
# TITLE PAGE
# ═══════════════════════════════════════════════════════════════════════════════
story.append(Spacer(1, 1.5*cm))
story.append(Paragraph("Spontaneous Resolution of Subdural Hematoma", title_style))
story.append(Paragraph("and Coagulopathy in Trauma Patients", title_style))
story.append(Spacer(1, 0.3*cm))
story.append(HRFlowable(width="100%", thickness=2, color=GOLD))
story.append(Spacer(1, 0.3*cm))
story.append(Paragraph("Theories, Mechanisms and Clinical Implications", subtitle_style))
story.append(Spacer(1, 0.2*cm))
story.append(Paragraph("A Comprehensive Review from Neurosurgery Textbooks and Published Literature", subtitle_style))
story.append(Spacer(1, 0.3*cm))
story.append(Paragraph("Compiled: July 2026  |  Sources: Neurosurgery, Forensic Pathology, Anaesthesia Textbooks + PubMed", date_style))
story.append(Spacer(1, 1*cm))

# ── Table of Contents ──────────────────────────────────────────────────────────
toc_data = [
    ["SECTION", "TOPIC"],
    ["1", "Introduction and Overview"],
    ["2", "Spontaneous Resolution of Acute SDH"],
    ["  2.1", "Mechanism 1 — CSF Washout via Arachnoid Tear"],
    ["  2.2", "Mechanism 2 — Redistribution and Migration"],
    ["  2.3", "Mechanism 3 — Coagulopathy-Facilitated Resolution"],
    ["3", "Chronic SDH: Biological Organization and Resorption"],
    ["  3.1", "Histological Timeline of Hematoma Organization"],
    ["  3.2", "SDH → Hygroma Transformation"],
    ["4", "Predisposing Factors for Spontaneous Resolution"],
    ["5", "Trauma-Induced Coagulopathy (TIC): Mechanisms"],
    ["  5.1", "Acute Traumatic Coagulopathy (ATC)"],
    ["  5.2", "APC Pathway (Primary Mechanism)"],
    ["  5.3", "DIC Hypothesis"],
    ["  5.4", "Glycocalyx Shedding"],
    ["  5.5", "Resuscitation-Associated Coagulopathy (RAC)"],
    ["6", "Spontaneous Resolution of Coagulopathy"],
    ["7", "Summary Comparison Tables"],
    ["8", "Clinical Implications and Warnings"],
    ["9", "References"],
]
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story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 1 — INTRODUCTION
# ═══════════════════════════════════════════════════════════════════════════════
story.append(Paragraph("1.  Introduction and Overview", h1_style))
story.append(Paragraph(
    "Subdural hematoma (SDH) is one of the most clinically significant intracranial injuries encountered "
    "after head trauma. Classically managed with surgical evacuation when causing mass effect or neurological "
    "deterioration, a subset of SDHs — across all subtypes (acute, subacute, and chronic) — undergoes "
    "<b>spontaneous resolution without surgical intervention</b>. This phenomenon, variably termed "
    "<i>auto-decompression</i>, spontaneous regression, or non-operative resolution, has been increasingly "
    "documented since the first systematic descriptions in the late 1980s.",
    body_style))
story.append(Paragraph(
    "Closely related is the phenomenon of <b>trauma-induced coagulopathy (TIC)</b>, which affects up to 25% "
    "of major trauma patients on hospital arrival and is an independent predictor of mortality. Understanding "
    "the mechanisms by which both SDH and TIC resolve spontaneously has significant clinical, prognostic, "
    "and medico-legal implications.",
    body_style))
story.append(Paragraph(
    "This document synthesises current evidence from neurosurgery and forensic pathology textbooks "
    "(DiMaio's Forensic Pathology 3rd Ed, Miller's Anesthesia 10th Ed, Fischer's Mastery of Surgery 8th Ed, "
    "Current Surgical Therapy 14th Ed, Essentials of Forensic Medicine and Toxicology 36th Ed, Adams and Victor's "
    "Neurology 12th Ed) alongside peer-reviewed PubMed publications through 2025.",
    body_style))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 2 — SPONTANEOUS RESOLUTION OF ACUTE SDH
# ═══════════════════════════════════════════════════════════════════════════════
story.append(Paragraph("2.  Spontaneous Resolution of Acute SDH", h1_style))
story.append(Paragraph(
    "Acute SDH results from bridging vein rupture or cortical arterial bleeding, typically accumulating "
    "in the crescent-shaped subdural space. Although prompt surgical evacuation remains the standard of care "
    "when mass effect or neurological decline is present, a clinically important minority of patients experience "
    "rapid or gradual spontaneous resolution. The following mechanisms have been identified or postulated.",
    body_style))

# 2.1
story.append(Paragraph("2.1  Mechanism 1 — CSF Washout via Arachnoid Tear", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "This is the most widely supported and best-documented mechanism for <b>rapid</b> (hours to 48 hours) "
    "spontaneous resolution of acute SDH.",
    body_style))
story.append(Paragraph("Pathophysiology:", bold_body))
bullets_csf = [
    "Traumatic force tears the arachnoid membrane, creating an abnormal communication between the "
    "subarachnoid space and the subdural hematoma cavity.",
    "CSF, which is normally under positive pressure in the subarachnoid space, enters the subdural "
    "compartment through the arachnoid defect.",
    "The influx of CSF dilutes the hematoma contents and disperses the blood along the subdural space "
    "and into other CSF pathways — effectively 'washing out' the clot.",
    "The hematoma is replaced by CSF, resulting in a <b>subdural hygroma</b> — a collection of clear "
    "or xanthochromic fluid with no mass effect.",
    "The hygroma may itself resolve with time or may persist, requiring follow-up imaging.",
]
for b in bullets_csf:
    story.append(Paragraph(f"\u2022  {b}", bullet_style))

story.append(Spacer(1, 6))
story.append(Paragraph("Key Evidence:", bold_body))
story.append(Paragraph(
    "Gelsomino et al. (2018, World Neurosurgery, PMID 29660550) reported a 25-year-old male who "
    "presented after a head-on motor vehicle collision with an acute left-sided SDH causing 11 mm "
    "of midline shift. The hematoma resolved completely within 48 hours and was replaced by a thin "
    "subdural hygroma. The imaging evolution directly demonstrated the CSF washout mechanism. "
    "The authors concluded that CSF influx through an arachnoid tear is the primary driver of rapid "
    "acute SDH resolution.",
    body_style))
story.append(Paragraph(
    "Lee et al. further proposed that a significant proportion of <i>chronic</i> subdural hematomas "
    "actually originate as subdural hygromas (not organized acute hematomas), lending further support "
    "to the biological importance of the hygroma pathway in SDH natural history. "
    "(DiMaio's Forensic Pathology, 3rd Ed, p.144)",
    body_style))

# 2.2
story.append(Paragraph("2.2  Mechanism 2 — Redistribution and Migration", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "In severe polytrauma, particularly with coexisting skull fractures or prior craniotomy, the hematoma "
    "may redistribute rather than resorb. Several sub-mechanisms are postulated:",
    body_style))
redistrib = [
    ("<b>Cranio-spinal redistribution:</b> Blood migrates from the intracranial subdural space downward "
     "into the spinal subdural compartment through the foramen magnum, effectively reducing the "
     "intracranial volume and improving mass effect."),
    ("<b>Fracture-site egress:</b> Skull fractures, particularly linear or diastatic fractures, provide "
     "physical pathways for hematoma contents to decompress into the subgaleal or extracranial space. "
     "This is particularly relevant in paediatric patients with incomplete ossification and in severe "
     "polytrauma with multiple fractures."),
    ("<b>Brain re-expansion:</b> In patients with pre-existing cerebral atrophy (elderly, chronic alcoholics, "
     "patients with prior craniotomy), the brain can progressively re-expand into the vacated subdural space "
     "as intracranial pressure normalises, mechanically occupying the space previously held by the hematoma "
     "and preventing re-accumulation."),
    ("<b>Dural sinusoidal absorption:</b> Some authors propose that sinusoidal venous networks within the "
     "dural vasculature can absorb hematoma contents actively, especially for thinner, less-organised "
     "collections."),
]
for b in redistrib:
    story.append(Paragraph(f"\u2022  {b}", bullet_style))

story.append(Spacer(1, 6))
story.append(Paragraph("Key Case Evidence:", bold_body))
story.append(Paragraph(
    "Kwon, Hwang, and Shin (2021, Korean Journal of Neurotrauma, PMID 34760828) reported a 76-year-old "
    "male with a massive right-sided ASDH and significant midline shift. Based on preserved neurological "
    "status (GCS 14), surgery was deferred. Follow-up CT at 32 hours post-injury revealed near-total "
    "resolution of the hematoma — a finding the treating surgeons described as 'unexpected'. The authors "
    "performed a review of similar published cases and attributed the resolution to a combination of "
    "redistribution mechanisms and brain re-expansion in an atrophic brain.",
    body_style))
story.append(Paragraph(
    "Punia et al. (2024, Journal of Emergencies, Trauma and Shock, PMID 39911468) documented complete "
    "spontaneous resolution within 6 hours in an 11-month-old infant with acute left temporoparietal SDH "
    "following a fall. The paediatric skull's compliance and incomplete ossification were cited as "
    "key facilitating factors.",
    body_style))

# 2.3
story.append(Paragraph("2.3  Mechanism 3 — Coagulopathy-Facilitated Resolution (Auto-Decompression)", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "This mechanism specifically connects the two topics of this review. In severe polytrauma with "
    "<b>acute traumatic coagulopathy (ATC)</b>, the systemic fibrinolytic state can paradoxically "
    "facilitate SDH clearance:",
    body_style))
coag_mech = [
    "ATC drives hyperfibrinolysis via activated Protein C (APC) degradation of Plasminogen Activator "
    "Inhibitor-1 (PAI-1), resulting in unopposed tissue plasminogen activator (tPA) activity and "
    "elevated plasmin levels.",
    "Plasmin actively lyses newly formed fibrin clots in the subdural space, preventing the "
    "hematoma from consolidating into a firm, adherent clot.",
    "The remaining liquid blood component is more readily dispersed via the CSF washout and "
    "redistribution mechanisms described above.",
    "Additionally, skull fractures in the same polytrauma patient provide physical exit routes "
    "for the liquefied hematoma contents.",
    "This creates a scenario where coagulopathy — normally a dangerous complication in TBI — "
    "paradoxically contributes to hematoma clearance in a minority of patients.",
]
for b in coag_mech:
    story.append(Paragraph(f"\u2022  {b}", bullet_style))

story.append(Spacer(1, 6))
story.append(Paragraph(
    "Obeng-Gyasi et al. (2025, International Journal of Surgery Case Reports, PMID 39893963) "
    "described a 40-year-old male with bilateral acute SDH, multiple skull fractures, seizure history, "
    "and acute coagulopathy following a ladder fall (GCS 5 at presentation). Within 24 hours his GCS "
    "improved to 9T, and repeat CT at 72 hours showed complete resolution of bilateral SDH without surgery. "
    "The authors highlighted the interplay between coagulopathy, skull fractures, and prior craniotomy "
    "history as the syndromic basis for what they termed 'auto-decompression.'",
    body_style))

story.append(Paragraph(
    "<b>Important caveat:</b> The coagulopathy paradox should never justify withholding coagulopathy "
    "correction. Uncorrected ATC dramatically worsens TBI outcomes and can cause rapid SDH re-expansion "
    "from neo-membrane sinusoidal bleeding. This mechanism is an observed phenomenon in a subset of patients, "
    "not a therapeutic strategy.",
    box_style))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 3 — CHRONIC SDH RESORPTION
# ═══════════════════════════════════════════════════════════════════════════════
story.append(PageBreak())
story.append(Paragraph("3.  Chronic SDH: Biological Organisation and Resorption", h1_style))
story.append(Paragraph(
    "For chronic SDH, spontaneous resolution occurs through a different, more protracted pathway "
    "driven by the dura mater's organisational response. The subdural space has inherently limited "
    "absorptive capacity; therefore removal of a hematoma requires active biological remodelling "
    "rather than passive fluid reabsorption. (DiMaio's Forensic Pathology, 3rd Ed)",
    body_style))

# 3.1 Timeline table
story.append(Paragraph("3.1  Histological Timeline of Hematoma Organisation", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))

timeline_data = [
    ["TIME AFTER BLEED", "PATHOLOGICAL EVENT"],
    ["~24 hours",
     "Layer of fibrin deposited on the dural surface beneath the hematoma. "
     "Clot initially not adherent to dura."],
    ["36 hours",
     "Fibroblastic activity begins at the dura-hematoma junction. A layer of "
     "fibroblasts 2–5 cells thick forms."],
    ["4–5 days",
     "Clot begins adherence to the dura at multiple sites. Fibroblast layer thickens."],
    ["5–10 days",
     "Capillary and fibroblast invasion into the hematoma is evident. "
     "Haemosiderin-laden macrophages become obvious. Erythrocytes begin to 'lake' (lyse)."],
    ["8 days",
     "Neo-membrane 12–14 cells thick is present on the dural surface. "
     "Neocapillaries in this membrane are the source of potential rebleeding."],
    ["~14 days",
     "Arachnoid-side membrane begins forming. Dural membrane is now well-established."],
    ["3–4 weeks",
     "The outer membrane becomes thick and gelatinous. Haemolysed blood takes "
     "on a 'motor oil' appearance (red-brown, thick)."],
    ["Weeks to months",
     "Progressive resorption continues. Eventually complete resorption occurs, "
     "leaving only a gold/rust-coloured fibrotic membrane adherent to the dura — "
     "the textbook endpoint of resolved chronic SDH."],
]
tl_table = Table(timeline_data, colWidths=[3.5*cm, 12*cm])
tl_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), DARK_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), colors.white),
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story.append(tl_table)
story.append(Spacer(1, 6))
story.append(Paragraph(
    "Source: DiMaio's Forensic Pathology, 3rd Edition, p.144; "
    "Essentials of Forensic Medicine and Toxicology, 36th Ed (2026)",
    caption_style))

story.append(Paragraph(
    "The neo-membrane formed during organisation is highly vascular on its dural aspect. "
    "The thin-walled sinusoidal vessels within this membrane are prone to rupture and are the "
    "source of <b>rebleeding into chronic SDH</b> — either spontaneously or following even minor "
    "re-injury. This explains why chronic SDH can expand despite successful initial non-operative "
    "management, and why serial imaging is mandatory.",
    body_style))

# 3.2 Hygroma
story.append(Paragraph("3.2  SDH to Subdural Hygroma Transformation", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "A subdural hygroma is an accumulation of CSF (sometimes xanthochromic) within the subdural space. "
    "It represents an intermediate or endpoint of the spontaneous SDH resolution pathway:",
    body_style))
hygroma_bullets = [
    "Trauma tears the arachnoid → CSF leaks into subdural space → hygroma forms",
    "Blood from the original hematoma mixes with CSF → xanthochromic appearance",
    "If CSF efflux exceeds reabsorption capacity, the hygroma enlarges and can mimic SDH "
    "on imaging",
    "Alternatively, the hygroma is gradually reabsorbed and the patient recovers completely",
    "Some authors (Lee et al.) argue the majority of chronic SDHs originate as hygromas, "
    "not as organised acute hematomas — making the hygroma pathway a dominant route in "
    "the natural history of SDH",
]
for b in hygroma_bullets:
    story.append(Paragraph(f"\u2022  {b}", bullet_style))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 4 — PREDISPOSING FACTORS
# ═══════════════════════════════════════════════════════════════════════════════
story.append(Paragraph("4.  Predisposing Factors for Spontaneous SDH Resolution", h1_style))
pred_data = [
    ["FACTOR", "MECHANISM FACILITATED"],
    ["Young age / intact brain",
     "Higher intracranial compliance; strong pressure gradients favour redistribution; intact auto-regulation"],
    ["Paediatric patients",
     "Incomplete skull ossification = additional compliance; very thin arachnoid more prone to "
     "tearing (CSF washout). Resolution within hours documented (Punia 2024)."],
    ["Pre-existing cerebral atrophy",
     "Elderly/alcoholic: initially accommodates large hematoma; subsequently brain re-expands "
     "into vacated subdural space."],
    ["Coexisting skull fractures",
     "Physical channels for hematoma redistribution extracranially or into other compartments."],
    ["Arachnoid tears",
     "Direct pathway for CSF washout mechanism; conversion to hygroma."],
    ["Thin / isodense / acute hematoma",
     "Greater liquid component; less organised clot; more easily dispersed."],
    ["Prior craniotomy",
     "Altered dural architecture; reduced resistance to redistribution."],
    ["Acute coagulopathy / hyperfibrinolysis",
     "Prevents clot consolidation; maintains hematoma in liquid phase; paradoxically facilitates dispersal."],
    ["Anticoagulant use",
     "Impairs clot solidification; hematoma remains fluid and redistributes more readily "
     "(though also worsens bleeding risk)."],
]
pred_table = Table(pred_data, colWidths=[4.5*cm, 11*cm])
pred_table.setStyle(TableStyle([
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story.append(pred_table)

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 5 — TRAUMA-INDUCED COAGULOPATHY
# ═══════════════════════════════════════════════════════════════════════════════
story.append(PageBreak())
story.append(Paragraph("5.  Trauma-Induced Coagulopathy (TIC): Mechanisms", h1_style))
story.append(Paragraph(
    "TIC is a <i>\"multifactorial, global failure of the coagulation system to sustain adequate haemostasis "
    "after major trauma.\"</i> (Miller's Anesthesia, 10th Ed). It is present in up to 25% of severely injured "
    "patients on hospital arrival and carries an approximately 4-fold increase in mortality compared to "
    "trauma patients without coagulopathy. TIC comprises two distinct but overlapping entities:",
    body_style))

tic_overview = [
    ["ENTITY", "MECHANISM", "ONSET", "PRIMARY DRIVER"],
    ["Acute Traumatic Coagulopathy (ATC)",
     "Endogenous, injury and shock-driven; activated Protein C pathway, DIC, glycocalyx shedding",
     "Minutes after injury",
     "Tissue injury + hypoperfusion"],
    ["Resuscitation-Associated Coagulopathy (RAC) / Iatrogenic TIC",
     "Dilution of clotting factors, enzymatic impairment from hypothermia/acidosis, hypocalcaemia",
     "With/after resuscitation",
     "Crystalloid over-resuscitation, cold blood products"],
]
tic_table = Table(tic_overview, colWidths=[3.5*cm, 6*cm, 2.5*cm, 3.5*cm])
tic_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), DARK_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), colors.white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,0), 9),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [LIGHT_BLUE, colors.white]),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("FONTSIZE",      (0,1), (-1,-1), 9),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ("GRID",          (0,0), (-1,-1), 0.4, RULE_COLOR),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
]))
story.append(tic_table)
story.append(Spacer(1, 10))

# 5.1
story.append(Paragraph("5.1  Acute Traumatic Coagulopathy (ATC)", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "ATC is an <b>endogenous, early-onset</b> coagulopathy driven by the combination of direct tissue "
    "injury and haemodynamic shock. It is distinct from RAC and precedes any resuscitative intervention. "
    "Several mechanisms have been proposed, often operating simultaneously.",
    body_style))

# 5.2
story.append(Paragraph("5.2  APC Pathway — The Dominant Mechanism", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "This is the best-supported mechanism for early ATC and is considered the primary driver by most "
    "current authorities. (Fischer's Mastery of Surgery 8e; Miller's Anesthesia 10e; Current Surgical "
    "Therapy 14e)",
    body_style))

apc_steps = [
    ("Step 1", "Trauma + tissue hypoperfusion/shock → excess thrombin generation at the site of injury."),
    ("Step 2", "Thrombin binds to endothelial <b>thrombomodulin</b> → forms the thrombin-thrombomodulin "
               "complex. (Thrombomodulin is upregulated in response to hypoperfusion and vascular injury.)"),
    ("Step 3", "The complex activates <b>Protein C</b> → generates <b>Activated Protein C (APC)</b> "
               "in high concentrations."),
    ("Step 4", "APC inactivates <b>Factor Va</b> and <b>Factor VIIIa</b> — key cofactors of the intrinsic "
               "and common coagulation pathways — thereby suppressing thrombin generation."),
    ("Step 5", "APC also degrades <b>Plasminogen Activator Inhibitor-1 (PAI-1)</b> → PAI-1 can no longer "
               "suppress tissue plasminogen activator (tPA) → <b>hyperfibrinolysis</b> results from "
               "unopposed plasmin activity."),
    ("Net result", "Hypocoagulable state with enhanced fibrinolysis → impaired clot formation and "
                   "rapid lysis of any clots that do form. D-dimer elevated; fibrinogen consumed; PT/INR prolonged."),
]
apc_table_data = [["STEP", "EVENT"]] + [[s, d] for s, d in apc_steps]
apc_table = Table(apc_table_data, colWidths=[2.5*cm, 13*cm])
apc_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), MID_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), colors.white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,0), 9),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [colors.white, ACCENT]),
    ("FONTNAME",      (0,1), (0,-1), "Helvetica-Bold"),
    ("FONTNAME",      (1,1), (1,-1), "Helvetica"),
    ("FONTSIZE",      (0,1), (-1,-1), 9),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ("GRID",          (0,0), (-1,-1), 0.4, RULE_COLOR),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
]))
story.append(apc_table)
story.append(Spacer(1, 8))

# 5.3
story.append(Paragraph("5.3  DIC Hypothesis", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "The DIC hypothesis posits that severe trauma triggers massive activation of the coagulation cascade "
    "via Tissue Factor (TF) release, leading to consumptive coagulopathy. Key features include:",
    body_style))
dic_bullets = [
    "Massive TF release from injured tissues (especially TBI: disrupted blood-brain barrier releases "
    "neuronal TF into systemic circulation, potentiating TIC and worsening haemostasis)",
    "Activation of both intrinsic and extrinsic coagulation pathways → thrombin burst",
    "Fibrinogen consumed → low plasma fibrinogen levels",
    "Platelets activated and consumed → thrombocytopaenia",
    "Low Factors V, VIII → prolonged aPTT and PT",
    "Disproportionate plasmin elevation relative to thrombin → secondary hyperfibrinolysis",
    "Elevated fibrin degradation products (FDPs) and D-dimer",
    "Within 24 hours of severe trauma (ISS >16), almost all patients meet ISTH criteria for "
    "'overt DIC' or 'non-overt DIC' (Miller's Anesthesia, 10e)",
    "Note: Evidence for classic microvascular thrombosis and platelet consumption as in septic DIC "
    "is weaker in trauma — the predominant phenotype is <i>fibrinolytic DIC</i>, not thrombotic DIC",
]
for b in dic_bullets:
    story.append(Paragraph(f"\u2022  {b}", bullet_style))

# 5.4
story.append(Paragraph("5.4  Glycocalyx Shedding — Autoheparinisation", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "The endothelial glycocalyx is a surface layer of glycoproteins, proteoglycans and glycosaminoglycans "
    "(including heparan sulphate) that normally lines the vascular lumen. It plays critical roles in "
    "haemostasis, vascular tone and inflammation.",
    body_style))
glyco_bullets = [
    "Haemodynamic shock and inflammatory mediators in severe trauma trigger shedding of the glycocalyx",
    "Heparan sulphate and other glycosaminoglycan anticoagulants are released into the systemic "
    "circulation → autoheparinisation",
    "Syndecan-1, a transmembrane glycoprotein and surrogate marker of glycocalyx degradation, is "
    "measurably elevated at admission in major trauma patients",
    "High admission syndecan-1 level strongly predicts mortality, coagulopathy, and need for "
    "massive transfusion (Miller's Anesthesia, 10e)",
    "Glycocalyx shedding is also associated with depletion of Protein C and activation of "
    "fibrinolysis — linking it mechanistically to the APC pathway",
    "Glycocalyx regeneration takes hours to days, explaining why coagulopathy may persist "
    "even after haemorrhage control and factor replacement",
]
for b in glyco_bullets:
    story.append(Paragraph(f"\u2022  {b}", bullet_style))

# 5.5
story.append(PageBreak())
story.append(Paragraph("5.5  Resuscitation-Associated Coagulopathy (RAC) — The Lethal Triad", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "RAC is an iatrogenic coagulopathy that develops as a consequence of resuscitative therapy for "
    "haemorrhagic shock. It is driven by three interrelated processes: <b>hypothermia, acidosis, and "
    "haemodilution</b> — collectively termed the 'Lethal Triad'. (Fischer's Mastery of Surgery, 8e; "
    "Current Surgical Therapy, 14e)",
    body_style))

lethal_data = [
    ["COMPONENT", "MECHANISM", "CLINICAL CORRELATE"],
    ["Hypothermia\n(< 34°C)",
     "Coagulation cascade enzymes are temperature-sensitive; each 1°C drop below normal "
     "significantly impairs factor activity. Platelet function also deteriorates. Cold blood "
     "products and crystalloids compound this.",
     "Impaired clot formation; prolonged PT/aPTT; platelet aggregation failure"],
    ["Acidosis\n(pH < 7.2)",
     "0.9% NaCl has pH 5.0; Lactated Ringer's pH 6.5 — both well below physiological pH 7.4. "
     "Acidaemia inhibits coagulation enzyme kinetics and impairs platelet activation.",
     "Prolonged clotting times; reduced fibrinogen polymerisation; impaired platelet function"],
    ["Haemodilution",
     "Crystalloid >2 L prehospital significantly increases coagulopathy risk; >4 L "
     "crystalloid raises risk regardless of admission lactate. Dilutes all clotting factors, "
     "fibrinogen, and platelets.",
     "Reduced factor concentrations; hypofibrinogenaemia; thrombocytopaenia"],
    ["Hypocalcaemia",
     "Calcium (Factor IV) is an essential cofactor for multiple steps in the coagulation "
     "cascade. Massive transfusion without calcium replacement causes iatrogenic hypocalcaemia.",
     "Impaired thrombin generation; prolonged clotting"],
]
lethal_table = Table(lethal_data, colWidths=[2.8*cm, 8*cm, 4.7*cm])
lethal_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), DARK_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), colors.white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,0), 9),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [colors.white, ACCENT]),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("FONTSIZE",      (0,1), (-1,-1), 8.5),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ("GRID",          (0,0), (-1,-1), 0.4, RULE_COLOR),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
]))
story.append(lethal_table)

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 6 — SPONTANEOUS RESOLUTION OF COAGULOPATHY
# ═══════════════════════════════════════════════════════════════════════════════
story.append(Paragraph("6.  Spontaneous Resolution of Coagulopathy", h1_style))
story.append(Paragraph(
    "Resolution of TIC follows correction of the underlying physiological drivers. In patients where "
    "haemorrhage is controlled and perfusion restored, the coagulopathy tends to resolve through "
    "the following mechanisms:",
    body_style))

res_data = [
    ["MECHANISM", "DETAIL"],
    ["Cessation of haemorrhage and restoration of perfusion",
     "Removes the hypoperfusion stimulus for thrombomodulin upregulation and APC generation. "
     "Thrombomodulin-thrombin complex formation diminishes as normal laminar flow resumes."],
    ["Factor replenishment (endogenous)",
     "The liver continuously synthesises coagulation factors. Once consumption stops, levels "
     "restore. Short-lived factors (Factor VII, t1/2 ~6 h) normalise fastest. Fibrinogen is "
     "an acute phase protein and can increase rapidly in response to injury signals."],
    ["Fibrinolysis normalisation",
     "As APC levels fall, PAI-1 activity recovers, suppressing tPA and plasmin. Fibrinolysis "
     "returns to baseline. Basis for tranexamic acid (TXA) therapy — given within 3 h of injury, "
     "blocks the hyperfibrinolytic arm without thrombotic risk."],
    ["Correction of hypothermia",
     "Active warming restores coagulation enzyme kinetics. Each degree of temperature rise "
     "meaningfully improves clot formation."],
    ["Correction of acidosis",
     "Avoidance of excessive crystalloid and use of balanced blood-based resuscitation "
     "(1:1:1 pRBC:plasma:platelets or whole blood) prevents acidosis. Isotonic balanced "
     "crystalloids (pH 7.4) are preferred if crystalloids must be used."],
    ["Correction of hypocalcaemia",
     "Calcium replacement during massive transfusion rapidly restores this cofactor."],
    ["Glycocalyx regeneration",
     "Takes hours to days. Syndecan-1 normalisation tracks with clinical recovery. Currently "
     "no pharmacological strategy to accelerate glycocalyx repair is in routine use."],
    ["TBI-specific delay",
     "In isolated TBI, ongoing BBB disruption continues feeding tissue factor systemically, "
     "and cerebral oedema perpetuates local coagulation activation. Coagulopathy in TBI is "
     "therefore more persistent and less predictable than in systemic trauma — resolution "
     "correlates with reduction in cerebral swelling."],
]
res_table = Table(res_data, colWidths=[4.5*cm, 11*cm])
res_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), DARK_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), colors.white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,0), 9.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [colors.white, ACCENT]),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("FONTSIZE",      (0,1), (-1,-1), 9),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ("GRID",          (0,0), (-1,-1), 0.4, RULE_COLOR),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 7),
    ("RIGHTPADDING",  (0,0), (-1,-1), 7),
]))
story.append(res_table)

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 7 — SUMMARY TABLES
# ═══════════════════════════════════════════════════════════════════════════════
story.append(PageBreak())
story.append(Paragraph("7.  Summary Comparison Tables", h1_style))

story.append(Paragraph("7A — Mechanisms of Spontaneous SDH Resolution", h2_style))
sum_sdh_data = [
    ["MECHANISM", "SDH TYPE", "TIMEFRAME", "KEY REFERENCE"],
    ["CSF washout via arachnoid tear\n→ Hygroma formation",
     "Acute SDH", "Hours–48 h",
     "Gelsomino et al. 2018\n(PMID 29660550)\nWorld Neurosurgery"],
    ["Redistribution / migration\n(fractures, spinal egress,\nbrain re-expansion)",
     "Acute SDH", "Hours–72 h",
     "Kwon et al. 2021\n(PMID 34760828)\nKorean J Neurotrauma"],
    ["Coagulopathy-facilitated\n(APC hyperfibrinolysis +\nskull fractures)",
     "Acute bilateral SDH\n+ polytrauma", "24–72 h",
     "Obeng-Gyasi et al. 2025\n(PMID 39893963)\nInt J Surg Case Rep"],
    ["Paediatric compliance\n(incomplete ossification)",
     "Acute SDH\n(paediatric)", "Within 6 h",
     "Punia et al. 2024\n(PMID 39911468)\nJ Emerg Trauma Shock"],
    ["Dura-driven organisation\n(fibroblast/capillary invasion,\nmacrophage clearance)",
     "Chronic SDH", "Weeks–months",
     "DiMaio's Forensic Pathology\n3rd Ed, p.144\nEssentials Forensic Med 36th Ed"],
]
sum_sdh_table = Table(sum_sdh_data, colWidths=[4*cm, 2.8*cm, 2.2*cm, 6.5*cm])
sum_sdh_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), DARK_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), colors.white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,0), 9),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [colors.white, ACCENT]),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("FONTSIZE",      (0,1), (-1,-1), 8.5),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ("GRID",          (0,0), (-1,-1), 0.4, RULE_COLOR),
    ("TOPPADDING",    (0,0), (-1,-1), 5),
    ("BOTTOMPADDING", (0,0), (-1,-1), 5),
    ("LEFTPADDING",   (0,0), (-1,-1), 6),
]))
story.append(sum_sdh_table)
story.append(Spacer(1, 14))

story.append(Paragraph("7B — Mechanisms of Trauma-Induced Coagulopathy and Resolution", h2_style))
sum_tic_data = [
    ["TIC MECHANISM", "KEY PATHWAY", "LABORATORY MARKER", "RESOLUTION STRATEGY"],
    ["APC activation",
     "Thrombomodulin-thrombin → APC → Factor Va/VIIIa degradation + PAI-1 inhibition → hyperfibrinolysis",
     "Low Factor V/VIII; elevated D-dimer; prolonged PT",
     "Restore perfusion; TXA within 3h; 1:1:1 resuscitation"],
    ["DIC (fibrinolytic type)",
     "Massive TF release → thrombin burst → fibrinogen/platelet consumption → secondary fibrinolysis",
     "Low fibrinogen; thrombocytopaenia; elevated FDPs",
     "FFP; cryoprecipitate; platelet transfusion; treat underlying cause"],
    ["Glycocalyx shedding",
     "Hypoperfusion → syndecan-1 release → heparan sulphate anticoagulation + PC depletion",
     "Elevated syndecan-1; associated with mortality",
     "Restore perfusion; glycocalyx regenerates over days"],
    ["Hypothermia",
     "Enzyme kinetics impaired < 34°C; platelet dysfunction",
     "Clinically measurable prolonged PT/aPTT on warm vs cold testing",
     "Active external/internal warming; warmed IV fluids"],
    ["Acidosis",
     "Low pH impairs coagulation enzyme activity",
     "ABG: metabolic acidosis; base deficit",
     "Avoid excess crystalloid; balanced resuscitation"],
    ["Haemodilution",
     "Crystalloid > 4 L dilutes all haemostatic components",
     "Low factor levels; low fibrinogen; dilutional thrombocytopaenia",
     "Limit crystalloid; use whole blood or 1:1:1 component therapy"],
    ["Hypocalcaemia",
     "Ca2+ deficiency disrupts multiple coagulation steps",
     "Ionised calcium < 1.1 mmol/L",
     "IV calcium replacement during transfusion"],
]
sum_tic_table = Table(sum_tic_data, colWidths=[3*cm, 5*cm, 3.5*cm, 4*cm])
sum_tic_table.setStyle(TableStyle([
    ("BACKGROUND",    (0,0), (-1,0), DARK_BLUE),
    ("TEXTCOLOR",     (0,0), (-1,0), colors.white),
    ("FONTNAME",      (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0), (-1,0), 8.5),
    ("ROWBACKGROUNDS",(0,1), (-1,-1), [colors.white, ACCENT]),
    ("FONTNAME",      (0,1), (-1,-1), "Helvetica"),
    ("FONTSIZE",      (0,1), (-1,-1), 8),
    ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ("GRID",          (0,0), (-1,-1), 0.4, RULE_COLOR),
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 5),
]))
story.append(sum_tic_table)

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 8 — CLINICAL IMPLICATIONS
# ═══════════════════════════════════════════════════════════════════════════════
story.append(PageBreak())
story.append(Paragraph("8.  Clinical Implications and Warnings", h1_style))

clin_points = [
    ("<b>Serial CT is mandatory</b> in all conservatively managed SDH patients, including those with apparent "
     "spontaneous resolution. Hygromas, re-expansion from neo-membrane sinusoidal bleeding, and conversion "
     "to chronic SDH are all recognised follow-up complications."),
    ("<b>Neurological reassessment must be continuous.</b> Given the unpredictable nature of TBI and the "
     "complex interplay of coagulopathy, fractures and physiology, even a clinically improving patient "
     "can deteriorate rapidly. (Obeng-Gyasi et al. 2025)"),
    ("<b>Coagulopathy must be corrected aggressively</b> in TBI — the coagulopathy paradox does not "
     "justify therapeutic permissiveness. Uncorrected ATC causes SDH expansion via neo-membrane "
     "neovascular rebleeding and worsens secondary injury."),
    ("<b>Monitor coagulation parameters</b> in all conservatively managed SDH patients. "
     "TEG/ROTEM provides the most clinically relevant assessment of the haemostatic state and "
     "guides targeted component replacement."),
    ("<b>Tranexamic acid (TXA)</b> given within 3 hours of head injury reduces mortality and head "
     "injury-related death (CRASH-3 trial) by blocking the hyperfibrinolytic arm of ATC. It does not "
     "increase the risk of thrombosis at this dosing window."),
    ("<b>Balanced blood-based resuscitation</b> (1:1:1 pRBC:plasma:platelets or whole blood) is the "
     "standard of care for haemorrhagic shock in trauma and prevents both dilutional coagulopathy "
     "and the acidosis/hypothermia of crystalloid over-resuscitation."),
    ("<b>In TBI specifically</b>, TIC persists longer than in systemic trauma because of ongoing "
     "BBB disruption and continuous TF release from injured neural tissue. Treatment targets for "
     "fibrinogen (>2 g/L) and platelets (>100 x10^9/L) are typically higher in TBI than in "
     "non-CNS trauma."),
    ("<b>Paediatric and elderly patients</b> are at opposite extremes of the spectrum: children may "
     "experience very rapid (hours) spontaneous resolution due to skull compliance; the elderly may "
     "have deceptively large hematomas accommodated by atrophy, masking clinical signs until late "
     "deterioration."),
    ("<b>Medico-legal note:</b> The histological timeline of SDH organisation (Section 3.1) is "
     "used in forensic pathology to estimate the timing of head trauma. The gold-coloured membrane "
     "at complete resorption is a recognised forensic endpoint."),
]
for b in clin_points:
    story.append(Paragraph(f"\u2022  {b}", bullet_style))
    story.append(Spacer(1, 3))

# ═══════════════════════════════════════════════════════════════════════════════
# SECTION 9 — REFERENCES
# ═══════════════════════════════════════════════════════════════════════════════
story.append(PageBreak())
story.append(Paragraph("9.  References", h1_style))
story.append(Spacer(1, 4))
story.append(Paragraph("Published Literature (PubMed)", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 6))

pubmed_refs = [
    "1.  Gelsomino M, Awad AJ, Gerndt C, et al. Mechanism for the Rapid Spontaneous Resolution of an Acute "
    "Subdural Hematoma and Transformation into a Subdural Hygroma. <i>World Neurosurgery</i>. 2018;116:e141–e147. "
    "DOI: 10.1016/j.wneu.2018.04.029. PMID: 29660550.",

    "2.  Kwon HC, Hwang YS, Shin HS. Rapid Spontaneous Resolution of Large Acute Subdural Hematoma. "
    "<i>Korean Journal of Neurotrauma</i>. 2021;17:e16. DOI: 10.13004/kjnt.2021.17.e16. PMID: 34760828. "
    "PMC: PMC8558017.",

    "3.  Obeng-Gyasi B, Chinthala AS, Christodoulides A, Ordaz J, Mao G. Rapid neurological recovery with "
    "spontaneous resolution of acute subdural hematoma after severe head trauma: A case report of "
    "auto-decompression phenomena. <i>International Journal of Surgery Case Reports</i>. 2025;118:110973. "
    "DOI: 10.1016/j.ijscr.2025.110973. PMID: 39893963. PMC: PMC11840520.",

    "4.  Punia P, Chugh A, Gotecha S, Singh N, Gaud J, Rege I. Rapid Spontaneous Regression of Traumatic "
    "Subdural Hematoma. <i>Journal of Emergencies, Trauma and Shock</i>. 2024;17:237–240. "
    "DOI: 10.4103/jets.jets_46_24. PMID: 39911468. PMC: PMC11792751.",

    "5.  Junior MGP, Pessoa BL, Landeiro JA, de Abreu Macedo PH, Leite MAA. Spontaneous resolution of chronic "
    "subdural hematoma: Does only the size matter? <i>Surgical Neurology International</i>. 2019;10:196. "
    "DOI: 10.25259/SNI_58_2019. PMID: 31637095. PMC: PMC6800287.",

    "6.  Yilmaz H, Boyali O, Atci IB. Spontaneous resolution of post-traumatic chronic subdural hematoma: "
    "a case report. <i>Pan African Medical Journal</i>. 2017;27:85. PMID: 29541313.",

    "7.  Fotso C, Sandberg DI. Spontaneous resolution of large subdural hematoma with midline shift: "
    "a case report. <i>Child's Nervous System</i>. 2021;37:633–637. DOI: 10.1007/s00381-020-04748-3. "
    "PMID: 32561984.",

    "8.  Piplani C, Gosselin A, Bargoud C, et al. Effect of Aging and Sex on Clot Formation, Structure, "
    "and Lysis in Trauma Patients. <i>Journal of the American College of Surgeons</i>. 2025 Aug 1. "
    "PMID: 39918217.",

    "9.  Moore EE, Moore HB, Kornblith LZ, et al. Trauma-induced coagulopathy. "
    "<i>Nature Reviews Disease Primers</i>. 2021;7(1):30. (Cited in Goldman-Cecil Medicine)",
]
for r in pubmed_refs:
    story.append(Paragraph(r, ref_style))
    story.append(Spacer(1, 3))

story.append(Spacer(1, 10))
story.append(Paragraph("Textbook Sources", h2_style))
story.append(HRFlowable(width="100%", thickness=0.8, color=RULE_COLOR))
story.append(Spacer(1, 6))

textbook_refs = [
    "10.  DiMaio VJ, DiMaio D. <i>DiMaio's Forensic Pathology</i>, 3rd Edition. CRC Press / Taylor & Francis; "
    "ISBN: 9780429318764. Chapter: Subdural Hematomas, pp. 144–146.",

    "11.  Pather R, Bhimji SS. <i>The Essentials of Forensic Medicine and Toxicology</i>, 36th Edition. "
    "Jaypee Brothers Medical Publishers; ISBN: 9789366165257. Section: Intracranial Haemorrhage, pp. 258–261.",

    "12.  Gropper MA (ed). <i>Miller's Anesthesia</i>, 2-Volume Set, 10th Edition. Elsevier; "
    "ISBN: 9780323935920. Chapter 25: Trauma-Induced Coagulopathy, pp. 9388–9395.",

    "13.  Fischer JE, Bland KI (eds). <i>Fischer's Mastery of Surgery</i>, 8th Edition. Wolters Kluwer / "
    "Lippincott Williams & Wilkins; ISBN: 9781975176433. Chapter: Trauma-Induced Coagulopathy, pp. 379–381.",

    "14.  Cameron JL, Cameron AM (eds). <i>Current Surgical Therapy</i>, 14th Edition. Elsevier; "
    "ISBN: 9780323796835. Chapter: Trauma-Induced Coagulopathy, pp. 1648–1654.",

    "15.  Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL (eds). "
    "<i>Bradley and Daroff's Neurology in Clinical Practice</i>, 8th Edition. Elsevier; "
    "ISBN: 9780323642613. Chapter: Subdural Hematoma.",

    "16.  Ropper AH, Samuels MA, Klein JP, Prasad S. <i>Adams and Victor's Principles of Neurology</i>, "
    "12th Edition. McGraw-Hill; ISBN: 9781264264520. Chapter: Spinal Subdural Haemorrhage, p. 813.",

    "17.  Marx J, Hockberger R, Walls R (eds). <i>Rosen's Emergency Medicine: Concepts and Clinical "
    "Practice</i>, 10th Edition. Elsevier; ISBN: 9780323757898.",

    "18.  Tietz NW (ed). <i>Tietz Textbook of Laboratory Medicine</i>, 7th Edition. Elsevier; "
    "ISBN: 9780323775724. Chapter: Disseminated Intravascular Coagulation.",

    "19.  Stern TA, Fava M, Wilens TE, Rosenbaum JF (eds). <i>Massachusetts General Hospital Comprehensive "
    "Clinical Psychiatry</i>. Chapter cited for DIC reference.",

    "20.  Sabiston DC (ed). <i>Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical "
    "Practice</i>, 21st Edition. Elsevier; ISBN: 9780443124341. Chapter: Disseminated Intravascular "
    "Coagulation.",
]
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story.append(Spacer(1, 10))
story.append(HRFlowable(width="100%", thickness=1, color=GOLD))
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story.append(Paragraph(
    "This document was compiled by Orris Medical Reference AI (July 2026) for educational purposes. "
    "All clinical decisions should be based on current guidelines and individual patient assessment.",
    caption_style))

# ── Build PDF ──────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF generated: {OUTPUT}")