Thrombophlebitis - A Comprehensive Review

1. ANATOMY

Lower Extremity Venous System

• Greater saphenous vein (GSV) - runs medially from the foot to the groin, joins the common femoral vein at the saphenofemoral junction (SFJ)
• Short (small) saphenous vein (SSV) - runs laterally, joins the popliteal vein at the saphenopopliteal junction (SPJ)
• Perforating veins - directly connect the saphenous system to the deep veins at various levels

• Common femoral vein (formed at inguinal ligament)
• Femoral vein (previously called "superficial femoral vein" - a confusing old term since it IS a deep vein)
• Popliteal vein (below adductor canal)
• Calf veins: anterior tibial, posterior tibial, and peroneal veins

"Distal greater saphenous vein thrombi are often referred to as superficial thrombosis, but greater saphenous clots near the connection with the femoral vein should be referred to as DVT." - Rosen's Emergency Medicine

• Distal DVT - calf veins only
• Proximal DVT - popliteal vein and above
• Iliofemoral DVT - femoral and iliac veins (highest risk)

Intracranial Venous Anatomy (for Suppurative Thrombophlebitis)

• Superior sagittal sinus - largest sinus; receives blood from frontal, parietal, and occipital superior cerebral veins and the diploic veins
• Transverse sinus - drains the superior sagittal sinus; also receives drainage from the middle ear and mastoid cells
• Sigmoid sinus - continuation of transverse sinus, drains into the internal jugular vein
• Cavernous sinus - at the skull base; receives blood from facial veins via the superior and inferior ophthalmic veins

2. PATHOLOGY (Virchow's Triad)

1. Endothelial Injury

• Most important factor in arterial thrombosis
• Injury exposes von Willebrand factor (vWF) and tissue factor
• Endothelial "activation" can occur from: physical injury, infections, cytokines, hypercholesterolemia, homocysteinemia, cigarette smoke toxins
• Activated endothelium: downregulates thrombomodulin, endothelial protein C receptor, TFPI; upregulates tissue factor and PAI (plasminogen activator inhibitors - inhibiting fibrinolysis)

2. Abnormal Blood Flow (Stasis / Turbulence)

• Stasis is the primary factor in venous thrombosis
• Stasis allows platelets and leukocytes to contact endothelium
• Slows the washout of activated clotting factors
• Prevents dilution by fresh flowing blood
• Common causes: prolonged immobility, heart failure, long-haul travel, varicose veins, pregnancy, cast immobilization

3. Hypercoagulability

• Prolonged bed rest / immobilization
• Surgery, fracture, burns
• Cancer (especially pancreatic, lung - Trousseau syndrome)
• Antiphospholipid syndrome
• Heparin-induced thrombocytopenia (HIT)
• Disseminated intravascular coagulation (DIC)
• Pregnancy / postpartum
• Oral contraceptive use

Thrombus Morphology

• Venous thrombi are red (red cell-rich) thrombi - formed under low flow, rich in red blood cells and fibrin
• They propagate in the direction of blood flow (proximally in legs)
• Fates: lysis, organization/recanalization, propagation, or embolism

3. MEDICINE (Clinical Presentation, Diagnosis, Treatment)

A. Superficial Thrombophlebitis (SVT)

• Tender, red, indurated cord following the line of a superficial vein
• Most commonly the GSV
• Prevalence: 3-11% of the general population
• Associated with: malignancy, obesity, thrombophilia, pregnancy, estrogen use, varicose veins, IV catheters, sclerotherapy

• Trousseau syndrome - migratory thrombophlebitis associated with occult malignancy (classically pancreatic or lung cancer)
• Mondor disease - SVT of the thoracoepigastric veins of the chest wall or breast; starts as a painful red cord, then becomes a painless fibrous band; 3x more common in women
• Thromboangiitis obliterans (Buerger disease) - recurrent SVT in young male smokers

• Duplex ultrasonography - confirms SVT, excludes DVT, assesses valve competence
• Thrombophilia workup is not routine but indicated for recurrent or idiopathic SVT
• Screen for malignancy if clinically suspected

• Distal/limited SVT: NSAIDs, leg elevation, warm compresses, ambulation, compression
• SVT within 5 cm of SPJ or 10 cm of SFJ: anticoagulation required
• First-line anticoagulants: fondaparinux (CALISTO trial - most evidence) or LMWH
• DOAC alternative: rivaroxaban 10 mg/day x 6 weeks was non-inferior to fondaparinux in the SURPRISE trial, and is more patient-friendly
• Septic SVT: broad-spectrum IV antibiotics; excision if patient becomes septic

B. Deep Vein Thrombosis (DVT)

• Classic: unilateral leg pain, swelling, erythema, warmth
• Up to 50% are asymptomatic
• Signs: Homan's sign (calf pain on dorsiflexion) - not reliable

• Duplex (compression + Doppler) ultrasound - first-line
• D-dimer - high negative predictive value; use with Wells score
• CT venography or MRI if iliac/IVC involvement suspected

• Anticoagulation for minimum 3-6 months (provoked) or longer/indefinitely (unprovoked)
• Preferred agents: DOACs (rivaroxaban, apixaban) - first-line in most patients
• LMWH preferred in cancer-associated thrombosis
• IVC filter only for contraindication to anticoagulation
• Compression stockings to prevent post-thrombotic syndrome

C. Suppurative (Septic) Thrombophlebitis

1. Peripheral septic SVT - usually from IV catheter infection (Staphylococcus aureus most common)
2. Intracranial suppurative thrombophlebitis - complication of sinusitis, otitis media, mastoiditis, or facial infections (Harrison's 22E)

• Superior sagittal sinus: headache, fever, seizures, stupor, bilateral leg weakness
• Cavernous sinus: CN III, IV, V, VI palsies; proptosis; chemosis; periorbital edema; fever

• IV antibiotics x 6 weeks (pathogen-directed)
• Heparin anticoagulation - recommended; small intracerebral hemorrhage is NOT an absolute contraindication
• Surgical debridement for septic lateral/cavernous sinus thrombosis
• Thrombolytics (rtPA) and thrombectomy: insufficient data to recommend routinely

4. SURGERY

A. Indications for Surgical Intervention

• Suppurative SVT not responding to antibiotics - the infected vein segment must be excised
• Recurrent SVT in varicose veins - high ligation/stripping of GSV eliminates the source

B. DVT Prophylaxis - Surgical Context

• Without prophylaxis, DVT incidence after knee arthroscopy ranges from 1.8% to 41.2% (average 6.8%)
• With prophylaxis, incidence drops to 0.1%-11.9% (average 1.8%)
• Recommended: sequential compression devices (SCDs) during surgery, early active ROM, and aspirin postoperatively when weight-bearing is altered
• High-risk patients (known thrombophilia, prior VTE, prolonged immobility): LMWH prophylaxis

• Endothelial injury - from the operation itself
• Stasis - from immobility, anesthesia, tourniquet use
• Hypercoagulability - from the inflammatory response to surgery

C. Postoperative Thrombophlebitis

• Aseptic SVT: local heat, elevation, NSAIDs
• Suppurative SVT: requires excision of the affected vein (not just antibiotics alone)
• Always evaluate for concurrent DVT in postoperative patients with SVT

D. Phlegmasia

• Phlegmasia alba dolens ("milk leg") - white, pale, edematous limb; collateral flow still present
• Phlegmasia cerulea dolens - blue, cyanotic, massively swollen limb; risk of venous gangrene if untreated; requires emergent CDT or surgical thrombectomy

Summary Table

• Robbins & Kumar Basic Pathology (Virchow's triad, hypercoagulability)
• Harrison's Principles of Internal Medicine 22E (suppurative thrombophlebitis)
• Rosen's Emergency Medicine (anatomy, DVT/PE pathophysiology)
• Fuster & Hurst's The Heart 15E (superficial thrombophlebitis management)
• Mulholland & Greenfield's Surgery 7E (SVT treatment, CALISTO/SURPRISE trials)
• Andrews' Diseases of the Skin (superficial thrombophlebitis, Mondor disease)
• Campbell's Operative Orthopaedics 15E 2026 (surgical prophylaxis)
• Tintinalli's Emergency Medicine (postoperative thrombophlebitis)

Dangerous Fungal Infections of the Human Body

Classification of Dangerous Fungi

1. INVASIVE CANDIDIASIS

Overview

Risk Factors

• ICU stay (>3 days)
• Broad-spectrum antibiotics (gut dysbiosis allows Candida overgrowth)
• Central venous catheters
• Total parenteral nutrition (TPN)
• Abdominal surgery / gut perforation
• Renal replacement therapy
• Hematological malignancy / bone marrow transplant
• Immunosuppression (steroids, chemotherapy)

Virulence Mechanisms

• Forms biofilms on prosthetic devices (resistant to antifungals)
• Hyphae (germ tubes) - allows tissue invasion
• Secretes proteases and phospholipases to damage host cells
• Phenotypic switching - changes surface antigens to evade immunity

Clinical Forms

Diagnosis

• Blood cultures (sensitivity ~50% - often misses deep infection)
• Beta-D-glucan assay (panfungal marker)
• Ophthalmology exam (all candidemic patients)
• CT chest/abdomen for organ involvement

Treatment

• Echinocandins (caspofungin, micafungin, anidulafungin) - first-line for most invasive candidiasis
• Fluconazole - step-down therapy for fluconazole-susceptible strains after clinical improvement
• Amphotericin B (liposomal) - for CNS candidiasis; C. krusei (intrinsically fluconazole resistant)
• Remove all central lines if possible
• Duration: minimum 14 days after last positive blood culture

2. INVASIVE PULMONARY ASPERGILLOSIS (IPA)

Overview

Pathogenesis

1. Hyphae germinate and invade pulmonary tissue
2. Hyphae penetrate alveolar capillaries and pulmonary arterioles (angioinvasion)
3. This causes intravascular thrombosis, local hypoxia, and coagulative necrosis (classic "infarct-like" lesions)
4. Hematogenous dissemination can reach the brain - a catastrophic complication

• Gliotoxin - inhibits macrophage phagocytosis and T-cell activation
• Elastase, phospholipase, proteases - aid tissue invasion
• Catalase - inactivates host-generated hydrogen peroxide (key in chronic granulomatous disease)

Risk Factors

• Prolonged severe neutropenia (acute myelogenous leukemia, hematopoietic cell transplant) - highest risk
• Hematopoietic stem cell transplant (HCT)
• Solid organ transplant (SOT) - especially lung transplant
• High-dose corticosteroids
• Chronic granulomatous disease (CGD)
• Advanced HIV
• Critically ill ICU patients (COPD, cirrhosis, severe influenza)
• Ibrutinib (Bruton tyrosine kinase inhibitor) therapy

Spectrum of Aspergillus Disease

Clinical Features (IPA)

• Fever not responding to antibiotics
• Pleuritic chest pain, hemoptysis
• Cough, dyspnea
• Halo sign on CT: nodule surrounded by ground-glass haze (early bleeding around infarcted area)
• Air crescent sign on CT: crescent of air around a necrotic nodule (late sign, seen with neutrophil recovery)

Diagnosis

• HRCT chest (halo sign, wedge-shaped infarcts, nodules)
• Galactomannan assay - serum and/or BAL (sensitivity ~80% in neutropenic patients)
• Beta-D-glucan
• Bronchoscopy with BAL - culture + cytology
• Tissue biopsy - definitive (septate hyphae with acute-angle branching at ~45°)
• Antifungal susceptibility testing - critical because azole-resistant A. fumigatus isolates are emerging (environmental resistance via fungicide use)

Treatment

• Voriconazole - first-line (oral/IV); superior to amphotericin in landmark RCT (Herbrecht 2002)
• Isavuconazole - alternative first-line; fewer drug interactions; better tolerated
• Liposomal amphotericin B (LAMB) 3-5 mg/kg/day - for azole-refractory or intolerant cases
• Echinocandins - salvage therapy only (fungistatic against Aspergillus, not fungicidal)
• Combination (voriconazole + anidulafungin) - considered in high-risk patients (subgroup data favorable)
• Surgical resection - for lesions adjacent to great vessels or with massive hemoptysis
• Duration: minimum 6-12 weeks; continue until immunosuppression resolved

3. MUCORMYCOSIS

Overview

Unique Risk Factors

• Diabetic ketoacidosis (DKA) - the most classic association
• Prolonged neutropenia / hematological malignancy
• Deferoxamine therapy (iron chelator provides iron to the fungus)
• Organ transplant
• Penetrating trauma / burns (cutaneous mucormycosis)
• Corticosteroid use (COVID-19 era)

Why DKA predisposes: High glucose and low pH impair neutrophil and macrophage function; elevated free iron (from acidosis) fuels fungal growth; iron-sequestration by deferoxamine paradoxically feeds the mold.

Clinical Forms

The "Black Eschar" Sign

Diagnosis

• CT/MRI of sinuses and brain - essential
• Tissue biopsy - definitive; shows broad, ribbon-like, aseptate hyphae with right-angle branching (contrasting with Aspergillus's acute-angle septate hyphae)
• Note: galactomannan and beta-D-glucan are negative in mucormycosis (major distinguishing feature from aspergillosis)

Treatment (triple approach - all three required simultaneously)

1. Antifungal: Liposomal amphotericin B 5-10 mg/kg/day (higher doses than for aspergillosis); isavuconazole or posaconazole as step-down/salvage therapy
2. Surgical debridement: Aggressive, often disfiguring. All necrotic tissue must be removed. May require orbital exenteration for orbital involvement
3. Reverse the underlying predisposition: Correct DKA, reduce/stop immunosuppression

• Voriconazole has no activity against mucorales - a critical distinction when empirically treating uncertain mold infections
• Mortality: 40-80% (rhinocerebral form); >90% (disseminated form)

4. CRYPTOCOCCOSIS

Overview

Virulence Mechanisms (Medical Microbiology 9e)

1. Polysaccharide capsule - the most important:
   • Physically blocks phagocytosis
   • Suppresses both cellular and humoral immunity
   • Inhibits antigen presentation to T cells
   • Depletes complement components
   • Reduces leukocyte migration
   • Electrostatic repulsion prevents effector cell binding
2. Melanin synthesis (via membrane-bound phenoloxidase):
   • Deposited in cell wall
   • Increases cell wall integrity
   • Protects against oxidative stress, temperature extremes, and microbicidal peptides
   • Responsible for neurotropism - why the organism has a predilection for the CNS
3. Growth at 37°C - survives at body temperature
4. Alpha-mating phenotype (MATalpha) - regulates capsule and melanin gene expression

Pathogenesis

• Inhaled as small yeasts or spores
• In the lung: alveolar macrophages attempt phagocytosis but cannot reliably kill the organism
• Cryptococci replicate inside mature phagolysosomes ("Trojan horse" mechanism)
• CD4+ T cells are critical to prevent dissemination - which explains why HIV patients with CD4 <100/µL are at highest risk
• Dissemination: macrophages carrying viable yeast travel from lung → lymphatics → bloodstream → brain (facilitated by melanin-mediated neurotropism)

Clinical Manifestations

• Often subacute (weeks of worsening headache)
• CSF: India ink prep shows encapsulated yeast; cryptococcal antigen (CrAg) titer - highly sensitive
• Raised intracranial pressure (ICP) is the leading cause of early death and neurological complications
• Management of raised ICP: serial lumbar punctures to remove CSF (target opening pressure <20 cmH₂O)

Treatment (HIV-associated cryptococcal meningitis)

1. Induction (2 weeks): Liposomal amphotericin B + flucytosine (5-FC) - superior to amphotericin alone
2. Consolidation (8 weeks): Fluconazole 400 mg/day
3. Maintenance: Fluconazole 200 mg/day (until CD4 >200 for >6 months on ART)

• ICP management: serial therapeutic LPs; VP shunt in refractory cases
• Mortality: 20-40% even with optimal treatment in resource-rich settings; much higher in low-resource settings

5. HISTOPLASMOSIS (Disseminated)

Overview

Clinical Features (HIV-associated disseminated histoplasmosis)

• 96% of AIDS patients present with fever and weight loss
• ~10% present with a sepsis-like syndrome: hypotension, respiratory failure, liver and renal failure, DIC
• Most cases occur with CD4+ count <100 cells/µL (often <50)
• Lab: anemia, leukopenia, thrombocytopenia; elevated LDH and serum ferritin (often markedly elevated)
• Chest X-ray: diffuse coarse reticulonodular opacities (or normal in 35-55% of disseminated cases)

Diagnosis

• Histoplasma urine antigen - detected in 100% of AIDS patients with disseminated disease (serum 92%)
• Rising antigen levels = relapse; falling = treatment response
• Cross-reacts with blastomycosis, coccidioidomycosis (false positives)
• Culture (weeks for growth)

Treatment

• Liposomal amphotericin B (induction for severe disseminated disease)
• Itraconazole (step-down and maintenance)

6. PNEUMOCYSTIS JIROVECII PNEUMONIA (PCP)

• Risk: CD4 <200 cells/µL (prophylaxis indicated)
• Presentation: Subacute progressive dyspnea, dry cough, fever; bilateral interstitial infiltrates; elevated LDH
• Diagnosis: Bronchoalveolar lavage (BAL) with Giemsa, methenamine silver stain; beta-D-glucan elevated
• Treatment: TMP-SMX (first-line); add prednisone if PaO₂ ≤70 mmHg (reduces mortality)
• Mortality: 5-15% (with treatment); up to 40-60% (without treatment)

Antifungal Drug Summary

Who Is Most at Risk?

1. Neutropenia (especially prolonged, <500/µL) - key defense against molds (Aspergillus, Mucor)
2. CD4 T-cell deficiency (HIV, transplant) - key defense against Cryptococcus, Histoplasma, PCP
3. Loss of mucosal barriers (catheters, surgery, gut injury) - key risk for invasive Candida

Key Distinguishing Features at a Glance

• Murray & Nadel's Textbook of Respiratory Medicine (opportunistic mycoses, cryptococcosis, histoplasmosis)
• Medical Microbiology 9e (Cryptococcus neoformans virulence; Aspergillus pathogenesis)
• Current Surgical Therapy 14e (invasive candidiasis mortality data)
• Tietz Textbook of Laboratory Medicine 7e (candidemia bloodstream infection)
• Fitzpatrick's Dermatology (mucormycosis)