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Clinical Assessment: Phlebotomy for Tabassum Gori

Patient Summary

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Should You Do Phlebotomy?

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2025 ACC/AHA Guideline Position on Phlebotomy in Cyanotic ACHD

"Phlebotomy may be considered in patients with refractory symptoms of hyperviscosity syndrome after adequate hydration with oral or IV fluid and adequate correction of iron deficiency."

"Another indication for phlebotomy may be if the patient's hematocrit level is >65% [preoperatively for autologous blood transfusion]."

"Prophylactic phlebotomy should be avoided — it exacerbates iron deficiency and increases stroke risk. It should NOT be used as primary treatment in patients with hyperviscosity symptoms or in asymptomatic patients with elevated hematocrit, as the effect on hematocrit is transient."*

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Applying to This Patient

✅ Criteria Met for Phlebotomy

1. HCT 66.5% — crosses the >65% threshold
2. Hb 21.1 g/dL — severely elevated
3. Symptomatic: Fever, chills, rigors, bilateral lower limb edema — active clinical deterioration
4. SpO₂ 70% on RA — severe chronic hypoxemia driving erythrocytosis

⚠️ Critical Concerns Before/During Phlebotomy

1. COAGULOPATHY — Most Urgent Red Flag

• INR 3.77 (current) — severely elevated
• PT 47.7s, APTT 46.6s — both prolonged
• This is characteristic of the intrinsic hemostatic defect in Eisenmenger syndrome: thrombocytopenia tendency, dysfunctional platelets, and coagulation factor depletion
• Phlebotomy in this coagulopathic state carries significant bleeding risk
• Action: Investigate the cause of INR elevation — is she on anticoagulants? Warfarin? If so, what's the indication? Hepatic dysfunction from chronic right heart failure? Correct before phlebotomy if possible, or minimize volume removed

2. IRON DEFICIENCY — Must Rule Out First

• RDW 21.6 (markedly elevated) — strongly suggests mixed picture: secondary erythrocytosis + iron deficiency
• Peripheral smear shows macrocytes + ovalocytes — macrocytes could indicate B12/folate deficiency or dyserythropoiesis; ovalocytes can be seen in iron deficiency
• Paradox: HCT appears high (66.5%) but RDW elevation + morphological changes suggest relative iron deficiency
• Iron-deficient erythrocytes are less deformable, worsening hyperviscosity even at a "normal" HCT
• Iron deficiency in Eisenmenger is associated with worse outcomes
• Action: Check serum iron, ferritin, transferrin saturation BEFORE phlebotomy. If iron-deficient, repleting iron (carefully, with monitoring) may actually reduce HCT and symptoms more safely than phlebotomy

3. HYDRATION STATUS

• Rule out dehydration as a cause of falsely elevated HCT
• Fever + rigors suggest possible infection/sepsis → dehydration likely
• Action: Adequate oral/IV hydration first, recheck HCT after rehydration

4. ACTIVE INFECTION

• Current admission: fever, chills, rigors → sepsis workup is mandatory
• Source of infection? Blood cultures, urine culture, echo to rule out infective endocarditis (high risk in this patient with structural heart disease)
• Do not perform elective phlebotomy during active sepsis — stabilize infection first

5. THROMBOCYTOPENIA TREND

• Platelets declining: 242 (2023) → 194 (2024) → 165 (2026)
• Below 200 and trending down — platelet function is also abnormal in Eisenmenger
• Combined with INR 3.77 → bleeding risk from phlebotomy is substantial

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Protocol if Phlebotomy is Decided

• Volume: Remove 250–500 mL (not more) — minimum that achieves symptomatic relief
• Simultaneous volume replacement: Isotonic saline 250–500 mL (use 5% dextrose only if in heart failure to avoid fluid overload)
• Target HCT: Reduce to just below 65%, not normal range — do NOT aggressively drop HCT as this will worsen oxygen delivery
• Do NOT repeat routinely — each phlebotomy worsens iron deficiency and increases stroke risk
• After phlebotomy, check iron stores and replace iron if deficient

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Overall Recommendation

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A Note on SPO₂ 70%

• Optimizing PAH therapy (PDE5 inhibitors, endothelin receptor antagonists, prostanoids)
• Identifying if there is a residual/recurrent shunt
• Ensuring iron replete state

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Revised Management with Corrected Coagulation: PT 24.7s / INR 1.84

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What INR 1.84 Means in This Context

• Reduced clotting factor synthesis (chronic liver congestion from right heart failure)
• Qualitative platelet dysfunction
• Reduced von Willebrand factor high-molecular-weight multimers
• Paradoxically, also at risk for both thrombosis AND bleeding

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Revised Management Plan

Phlebotomy Decision: PROCEED — with conditions

• ✅ HCT 66.5% → above the >65% threshold
• ✅ Hb 21.1 g/dL → severely elevated
• ✅ Active symptoms (bilateral LL edema, fever, clinical deterioration)
• ✅ INR 1.84 — inherent Eisenmenger coagulopathy, not a contraindication
• ✅ SpO₂ 70% — erythrocytosis is compensatory but HCT >65% is now also a thrombohemorrhagic risk

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Stepwise Protocol

Step 1 — Before Phlebotomy (Do These First)

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Step 2 — Phlebotomy Technique

• Volume: Remove 250–500 mL (single unit) — start with 250 mL given mild coagulopathy
• Simultaneous replacement: Isotonic saline 250–500 mL IV, run concurrently (not after)
• If in heart failure: Use 5% dextrose instead of saline to avoid volume overload
• Target: Reduce HCT to just below 65% — do NOT target normal HCT; over-reduction worsens oxygen delivery at SpO₂ 70%
• Setting: Monitored bed, SpO₂ and BP monitoring throughout
• Do NOT repeat prophylactically — only repeat if symptoms of hyperviscosity recur AND iron replete AND HCT again >65%

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Step 3 — Iron Deficiency Management (Mandatory)

• RDW 21.6 + macrocytes + ovalocytes on smear → this patient almost certainly has coexisting iron deficiency masked by high absolute Hb
• Iron deficiency in Eisenmenger = independent predictor of adverse outcomes
• Repeated phlebotomy without iron repletion → worsens deformability of RBCs → paradoxically increases hyperviscosity symptoms despite lower HCT
• If ferritin is low/transferrin saturation <20%: oral iron (ferrous sulfate 200mg BD) — titrate carefully; monitor for rapid HCT rise
• If severe deficiency: IV iron (Ferric carboxymaltose) with cardiology supervision

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Step 4 — Address the Active Presentation

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Step 5 — Long-Term PAH Optimization

• Current PAH medications? If not on targeted therapy → start (PDE5i: sildenafil/tadalafil; ERA: bosentan/macitentan)
• 6-minute walk test + NT-proBNP + functional class assessment for risk stratification
• Heart-lung transplant evaluation if refractory

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Summary: What Changed with INR 1.84

Indications for Phlebotomy in Secondary Polycythemia

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The Fundamental Distinction

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A. Physiologically INAPPROPRIATE Secondary Polycythemia

Indications — Liberal

1. Symptomatic hyperviscosity — headache, dizziness, blurred vision, tinnitus, plethora, fatigue
2. HCT persistently >45% — target HCT 42–46% with regular phlebotomy
3. Prior to elective surgery — mandatory phlebotomy to reduce thrombotic/bleeding perioperative risk
4. Thrombotic risk reduction — these patients have increased risk of CVA, MI, DVT, PE
5. Temporary relief while definitive treatment of underlying cause is arranged (e.g. tumor resection)

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B. Physiologically APPROPRIATE Secondary Polycythemia

Indications — Restrictive (all 3 ideally present)

1. Symptomatic Hyperviscosity Syndrome

• Visual disturbances, blurred vision
• Severe headache
• Dizziness, vertigo, tinnitus
• Paresthesia, digital numbness
• Profound fatigue, reduced concentration
• ⚠️ Always rule out dehydration first — dehydration falsely elevates HCT and mimics hyperviscosity symptoms

2. HCT Threshold

• HCT >65% — at this level, compensatory benefit plateaus and hyperviscosity overrides O₂ delivery benefit
• Below 65%: viscosity is still within tolerable range; O₂ delivery benefit outweighs risk of phlebotomy

3. Iron-Replete State

• Must confirm iron sufficiency before proceeding
• Iron deficiency → rigid, non-deformable RBCs → worsened viscosity at same or even lower HCT
• Phlebotomy in iron-deficient patient = worsening of the very problem you're trying to treat
• Check ferritin, serum iron, TIBC before each session

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Additional Specific Indications (Any Type of Secondary Polycythemia)

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Absolute Contraindications / When NOT to Phlebotomize

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Phlebotomy Technique When Indicated

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Summary Table

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Thrombophilia

Definition

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Classification

I. Inherited (Primary) Thrombophilias

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A. Loss-of-Function Mutations (Anticoagulant Deficiencies)

Protein S is the cofactor for Protein C. Both are vitamin K–dependent. Important clinical consequence: warfarin-induced skin necrosis — warfarin drops Protein C and S faster than procoagulant factors (II, VII, IX, X), creating a transient prothrombotic window → always bridge with heparin 2–3 days before warfarin loading in these patients. (Quick Compendium of Clinical Pathology, 5th Ed.)

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B. Gain-of-Function Mutations (Procoagulant Excess)

1. Factor V Leiden (FVL) — Most Common Inherited Thrombophilia

• Mutation: c.1691G>A in FV gene → Arg506Gln substitution
• Mechanism: APC (activated protein C) normally cleaves FVa at Arg506 to inactivate it. The Gln substitution resists APC cleavage → FVa persists → 10-fold prolongation of APC inactivation → excess thrombin generation
• Prevalence: 3–5% in White/Northern European populations; nearly absent in African and Asian populations
• VTE risk:
  • Heterozygous: 5–10× increased relative risk; mean onset age 44 years
  • Homozygous: 10–50× increased; mean onset age 31 years
• Represents: ~25% of idiopathic VTE, 30–50% of recurrent VTE
• Note: Does NOT increase arterial thrombosis risk

2. Prothrombin G20210A Mutation

• Mutation: G→A substitution at nucleotide 20210 of prothrombin gene
• Mechanism: Gain-of-function → elevated plasma prothrombin levels → excess thrombin
• Prevalence: 1–6% in White populations; rare in other groups
• Found in: 3–8% of all VTE patients; 2–3× increased VTE risk

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C. Other Inherited Procoagulant States

• Elevated Factor VIII — significant independent VTE risk factor; often genetically determined
• Factor IX Padua — X-linked thrombophilia (gain-of-function FIX mutation)
• Prothrombin Yukuhashi — rare missense mutation; impaired antithrombin inhibition of thrombin
• Elevated Factors VII, IX, XI, fibrinogen, vWF, thrombin-activatable fibrinolysis inhibitor (TAFI)
• ↓ Tissue Factor Pathway Inhibitor (TFPI)
• Rare: Heparin cofactor II deficiency, dysfunctional thrombomodulin, fibrinolytic disorders (hypoplasminogenemia, PAI-1 excess, dysplasminogenemia)

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II. Acquired (Secondary) Thrombophilias

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Antiphospholipid Syndrome (APS) — Key Acquired Thrombophilia

• Antibodies: Lupus anticoagulant (LA), anti-cardiolipin IgG/IgM, anti-β2 glycoprotein I IgG/IgM
• "Triple positive" (LA + 2 positive IgG antiphospholipid antibodies) = highest thrombotic risk
• Unique feature: Causes BOTH arterial AND venous thrombosis (unlike primary thrombophilias)
• Treatment: Warfarin preferred (not DOACs) for secondary prevention in APS, especially triple-positive; target INR 2.0–3.0
• Obstetric APS: Recurrent pregnancy loss, fetal loss, pre-eclampsia

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Clinical Manifestations

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Diagnosis — Who and When to Test

Who to Test

• Age <40 at first VTE
• Unprovoked VTE (no clear precipitant)
• Recurrent VTE
• Strong family history of thrombosis (first-degree relatives)
• Unusual site of thrombosis (cerebral, splanchnic)
• Pregnancy-associated thrombosis

• All patients after first VTE indiscriminately
• VTE with overt provoking factors (major surgery, trauma, prolonged immobility)
• Arterial thrombosis alone (primary thrombophilias are not the cause)

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When to Test — Timing Is Critical

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Laboratory Tests

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Treatment

Acute VTE

• Initial management is the same regardless of thrombophilia genotype
• DOACs (rivaroxaban, apixaban, edoxaban, dabigatran) — first-line; at least as effective as warfarin with fewer bleeds
• Exceptions where warfarin is preferred:
  • Antiphospholipid syndrome (especially triple-positive)
  • Prosthetic heart valves

Duration of Anticoagulation

Prophylaxis in High-Risk Situations

• Peripartum period
• Major surgery / prolonged immobilization
• Long-haul travel
• Hospitalization

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Summary: Risk Comparison

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Thrombophilia — Comprehensive Detail

Definition & Core Concept

"Similar to seizures, patients have a varying threshold for clotting." (Tintinalli's Emergency Medicine)

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Virchow's Triad — Pathophysiological Basis

1. Stasis — immobility, CHF, post-surgical, atrial fibrillation
2. Endothelial injury — atherosclerosis, trauma, surgery, hyperhomocysteinemia
3. Hypercoagulability — inherited or acquired thrombophilia

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PART I — INHERITED (PRIMARY) THROMBOPHILIAS

Physiologic Anticoagulant Systems (What Goes Wrong)

• ~2,000–4,000× for thrombin
• ~500–1,000× for Factor Xa
• ~1,000,000× for Factor IXa

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A. ANTITHROMBIN III DEFICIENCY

Types

Key Clinical Points

• Homozygous AT III deficiency is incompatible with life (intrauterine thrombosis) — except Type II HBS heterozygotes who survive
• Most common presentation: DVT lower extremity + PE; also retinal, mesenteric, splenic vein thrombosis
• Heparin resistance — heparin works through AT III; if AT III is absent/low, heparin cannot exert full anticoagulant effect → escalating heparin doses required → use AT III concentrate (recombinant or plasma-derived) as adjunct
• Acquired AT III deficiency: DIC, liver disease, nephrotic syndrome (urinary loss), post-thrombosis, asparaginase chemotherapy, heparin therapy (↓ up to 20%)
• Newborns have physiologically low AT III levels — reaches adult levels by 6 months

Diagnosis

• Functional (chromogenic) assay — preferred; detects all types including Type II
• Antigen assay (ELISA/nephelometry) — to distinguish Type I from Type II
• Never rely on antigen alone — Type II has normal antigen but low function

Treatment

• Acute VTE: standard anticoagulation; if heparin-resistant → AT III concentrate IV
• Long-term: DOACs or warfarin; indefinite anticoagulation after first unprovoked VTE recommended given very high recurrence risk

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B. PROTEIN C DEFICIENCY

Types

Key Clinical Points

• Neonatal purpura fulminans — homozygous or doubly heterozygous Protein C deficiency → widespread, potentially fatal thrombosis in newborns; a hematological emergency requiring Protein C concentrate
• Warfarin-induced skin necrosis (WISN) — the highest-risk thrombophilia for this complication:
  • Warfarin inhibits vitamin K–dependent proteins. Protein C has shortest half-life (~6–8 hours) → drops first, before procoagulant factors (II, VII, IX, X)
  • Creates a transient prothrombotic window of ~3–5 days after starting warfarin
  • Dermal venous thrombosis → painful skin necrosis, typically over fat-rich areas (breast, buttocks, thighs, abdomen)
  • Prevention: Always overlap with heparin (UFH or LMWH) for ≥5 days when initiating warfarin; avoid large loading doses
  • Management if occurs: Switch to heparin acutely; rivaroxaban shown safe as long-term alternative; Protein C concentrate if available
• Acquired Protein C deficiency: liver disease, DIC, vitamin K deficiency, post-op, neonatal period

Diagnosis

• Functional assay preferred (chromogenic or clot-based)
• Antigen assay to distinguish Type I from Type II
• Cannot test reliably during: acute thrombosis, warfarin therapy, vitamin K deficiency (all reduce Protein C)

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C. PROTEIN S DEFICIENCY

Types

Key Clinical Points

• In plasma, ~60% of Protein S is bound to C4b-binding protein (inactive); only the free form (~40%) is functionally active as Protein C cofactor
• Protein S deficiency mimics Protein C deficiency clinically — same sites of thrombosis
• Also associated with WISN (mechanism same as Protein C deficiency)
• Neonatal purpura fulminans in homozygous deficiency
• Acquired: liver disease, pregnancy, OCP/estrogen use (↑ C4b-binding protein → ↓ free fraction), Vitamin K deficiency, DIC

Diagnosis

• Free Protein S antigen — most important; reflects functionally available fraction
• Total Protein S antigen + functional assay to classify Type I/II/III
• Cannot test during: estrogen/OCP use, pregnancy, warfarin therapy, acute thrombosis

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D. FACTOR V LEIDEN (FVL) — Most Common Inherited Thrombophilia

Combined Risk (Multiplicative Effects)

Key Points

• Does NOT increase arterial thrombosis risk
• Found in 25% of idiopathic VTE, 30–50% of recurrent VTE, 20–60% of OCP-associated VTE, 8–30% of recurrent pregnancy loss

Diagnosis

• APCR phenotypic assay: ratio = APTT with APC ÷ APTT without APC; low ratio = resistance
  • Modified assay (1:5 dilution in FV-depleted plasma) is more specific for FVL
  • DOACs can falsely elevate APC ratio
• Molecular (PCR) testing for c.1691G>A — definitive; unaffected by anticoagulation; required to distinguish heterozygous from homozygous; critical for genetic counseling

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E. PROTHROMBIN G20210A MUTATION

Key Points

• Similar clinical phenotype to FVL — predominantly venous thrombosis
• Also associated with pregnancy complications (pre-eclampsia, fetal loss, IUGR)
• Combined FVL + prothrombin mutation = very high VTE risk
• Diagnosis: PCR for G20210A — lab tests of coagulation (PT/aPTT) may be normal; prothrombin activity/antigen elevated

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F. FACTOR II (PROTHROMBIN) DEFICIENCY — Hemorrhagic Disorder, NOT Thrombophilia

Types

Clinical Features

• Bleeding symptoms: mucosal bleeding (epistaxis, gum bleeding, menorrhagia), easy bruising, hematomas, hemarthrosis (joint bleeding)
• Severity correlates with residual FII activity level
• Dysprothrombinemia (Type II) is clinically milder and unpredictable

Lab Pattern

• Both PT and aPTT are prolonged because FII is in the common pathway (shared by intrinsic and extrinsic pathways)
• Compare: Factor VII deficiency → prolonged PT only (extrinsic); Factor VIII/IX deficiency → prolonged aPTT only (intrinsic)

Acquired Factor II Deficiency (More Common)

• Warfarin / Vitamin K deficiency — FII is vitamin K–dependent; drops with warfarin (half-life 3 days — slowest of all vitamin K–dependent factors)
• Liver disease — reduced hepatic synthesis
• DIC — consumption
• Antiphospholipid syndrome with lupus anticoagulant (LA) — rare acquired autoantibody can target prothrombin → lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) — causes bleeding despite a lupus anticoagulant (which usually causes thrombosis)

Treatment of FII Deficiency

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PART II — ACQUIRED (SECONDARY) THROMBOPHILIAS

Antiphospholipid Syndrome (APS) — Full Detail

Catastrophic APS (CAPS)

• Rapid multiorgan thrombosis (<1 week), high mortality
• Treat with anticoagulation + steroids + IVIG/plasmapheresis

Lab Paradox

• Lupus anticoagulant prolongs aPTT in vitro (phospholipid-dependent test) but causes thrombosis in vivo
• Cannot test lupus anticoagulant on DOACs — falsely positive results

Treatment

• Warfarin preferred over DOACs for APS (especially triple-positive) — target INR 2.0–3.0
• DOACs have shown higher recurrence rates in APS (TRAPS trial with rivaroxaban)

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Full Table of Acquired Thrombophilias (Secondary Hypercoagulable States)

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Thrombophilia Testing — Complete Framework

When to Suspect (Features)

• Age ≤45 at first VTE
• Recurrent VTE
• Family history of thrombosis (first-degree relatives)
• Unprovoked (no clear provoking factor)
• Unusual site: hepatic, portal, mesenteric, splenic, cerebral venous sinus
• Recurrent pregnancy loss / adverse obstetric outcomes
• Neonatal purpura fulminans
• Warfarin-induced skin necrosis

Testing Algorithm

When NOT to Test

• During acute thrombosis (consumes AT III, Protein C, Protein S — false deficiency)
• On warfarin (lowers Protein C, Protein S)
• On heparin (lowers AT III activity)
• On DOACs (interferes with LA testing, APCR ratio)
• Arterial thrombosis alone (primary thrombophilias rarely causative)

Optimal Timing

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Treatment — Comprehensive

Acute VTE

• DOACs first-line (rivaroxaban, apixaban, edoxaban, dabigatran) — at least as effective as warfarin, fewer bleeds
• Exceptions where warfarin preferred: APS (especially triple-positive), prosthetic heart valves, mechanical heart valves
• Bridge with UFH/LMWH for ≥5 days if starting warfarin in Protein C or S deficiency

Duration of Anticoagulation

Asymptomatic Relatives

• Do NOT anticoagulate prophylactically in absence of VTE history
• Counsel about: avoiding OCP/HRT, prophylaxis before surgery/pregnancy, signs of DVT/PE
• Test before planned hormone therapy or pregnancy if family member has high-risk thrombophilia

Pregnancy in Thrombophilia

• LMWH — anticoagulant of choice throughout pregnancy
• Warfarin: crosses placenta → fetal warfarin syndrome (teratogenic in 1st trimester), fetal bleeding
• DOACs: safety in pregnancy not established — avoid
• Thromboprophylaxis throughout pregnancy + 6 weeks postpartum (highest risk period) (Goldman-Cecil Medicine)

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Risk Summary — All Thrombophilias