The Patient with Recurrent DVTs: Unraveling the Hypercoagulable Workup

Dr Neeraj Manikath , claude.ai

Introduction: The Clinical Dilemma

A 42-year-old woman presents to your clinic. Three years ago, she developed a proximal DVT after a long-haul flight. She completed six months of anticoagulation. Eighteen months later, she had another unprovoked DVT, this time on the contralateral leg. Now on warfarin, she asks: "Why does this keep happening to me?"

This scenario is common yet complex. Venous thromboembolism (VTE) affects 1-2 per 1,000 individuals annually, with recurrence rates of 30% at 10 years after unprovoked events. The question facing clinicians is not just whether to test for thrombophilia, but when, what, how to interpret results, and most importantly—will it change management?

This guide provides a systematic approach to the hypercoagulable workup, focusing on high-yield diagnoses that alter treatment decisions, avoiding the "shotgun panel" approach that generates more confusion than clarity.

The Framework: When NOT to Test (Start Here)

Before discussing what to test, understand when testing is futile or potentially harmful.

Do NOT Test for Inherited Thrombophilia If:

1. Provoked VTE with transient risk factor:

Major surgery, trauma, immobilization >3 days, hospitalization
Pregnancy, puerperium, oral contraceptives, hormone replacement
Long-distance travel >6 hours

Rationale: Even if thrombophilia present, the provoking factor was the primary driver. Testing won't change the standard 3-month anticoagulation duration.

2. First unprovoked VTE in patients >50 years:

Age itself is a powerful risk factor (incidence increases 8-fold from age 40 to 80)
Inherited thrombophilias have diminishing clinical relevance with age
Acquired factors (malignancy, immobility, chronic disease) dominate

3. Decision for indefinite anticoagulation already made:

Recurrent unprovoked VTE (≥2 events)
Proximal DVT or PE with permanent risk factors (active cancer, antiphospholipid syndrome)

Pearl: If you're already planning lifelong anticoagulation, thrombophilia testing adds cost without benefit. Don't order tests that won't change management.

4. During acute thrombosis or on anticoagulation:

Many tests are falsely abnormal during acute events (Protein C, Protein S, Antithrombin)
Warfarin depletes Protein C and S (Vitamin K-dependent)
Heparin consumes Antithrombin
Direct oral anticoagulants (DOACs) interfere with functional assays

Exception: Genetic testing (Factor V Leiden, Prothrombin G20210A) can be done anytime, as DNA doesn't change. Antiphospholipid antibodies should be tested acutely and confirmed later.

The "Three Questions" Before Ordering Tests:

Will the result change duration of anticoagulation?
Will the result change choice of anticoagulant?
Will the result affect family counseling/screening?

If the answer to all three is "no," reconsider testing.

When TO Test for Thrombophilia: Clinical Scenarios

Scenario 1: Young Patient with Unprovoked VTE

Profile:

Age <45 years (some say <50)
First unprovoked proximal DVT or PE
No identifiable provoking factor
Contemplating stopping anticoagulation after 3-6 months

Rationale: Identifying high-risk thrombophilia (antithrombin deficiency, homozygous Factor V Leiden, compound heterozygotes) may justify indefinite anticoagulation.

Yield: ~15% will have identifiable inherited thrombophilia, but only 2-3% will be high-risk.

Scenario 2: Recurrent VTE (≥2 Events)

Profile:

Two or more objectively documented VTE events
At least one event unprovoked
Seeking explanation for recurrence

Rationale: While indefinite anticoagulation is typically warranted regardless of testing, patients and families often demand answers. Testing may identify acquired thrombophilias requiring specific therapy (APS, PNH, myeloproliferative neoplasms).

Oyster: Focus on acquired thrombophilias (APS, malignancy, MPN) rather than inherited. A patient with two unprovoked VTEs doesn't need Factor V Leiden testing—management is already clear.

Scenario 3: Thrombosis in Unusual Sites

Profiles:

Cerebral venous sinus thrombosis (CVST)
Splanchnic vein thrombosis (portal, mesenteric, splenic, hepatic veins)
Retinal vein occlusion
Bilateral simultaneous DVTs
Upper extremity DVT without catheter/pacemaker

Rationale: Unusual-site thromboses have higher association with underlying thrombophilia, particularly:

Paroxysmal nocturnal hemoglobinuria (PNH) → abdominal vein thrombosis
Myeloproliferative neoplasms → splanchnic thrombosis
Antiphospholipid syndrome → arterial AND venous thromboses

Hack: Splanchnic vein thrombosis = order JAK2 V617F and PNH flow cytometry immediately. These have high pretest probability and alter management.

Scenario 4: Warfarin-Induced Skin Necrosis

Profile:

Painful, purpuric skin lesions 3-7 days after starting warfarin
Typically affects breast, buttocks, thighs (high adipose tissue)
Patient may have DVT/PE that prompted warfarin initiation

Mechanism: Protein C deficiency (inherited or acquired). Protein C has the shortest half-life of Vitamin K-dependent factors (6-8 hours). Early warfarin effect depletes Protein C before Factors II, IX, X, creating transient hypercoagulable state.

Management:

Stop warfarin immediately
Vitamin K 10 mg IV
Therapeutic heparin/LMWH
Protein C concentrate if available (rare)
Surgical debridement if necrosis extensive

Testing: Protein C level (after acute event resolves, off anticoagulation x 2-4 weeks)

Pearl: Always "bridge" patients with heparin when starting warfarin, especially if known or suspected Protein C deficiency. DOACs do not cause this complication.

Scenario 5: Strong Family History

Profile:

Multiple first-degree relatives with VTE, especially if:
- Age <50 at first event
- Recurrent VTE
- Unusual-site thromboses

Rationale: High pretest probability of heritable thrombophilia. Identifying specific defect allows for:

Cascade screening of relatives
Counseling regarding pregnancy, OCPs, surgery
Risk stratification

Oyster: "My grandfather had a blood clot" is NOT a strong family history. You need multiple first-degree relatives with documented, objectively confirmed VTE at young ages.

Scenario 6: Pregnancy-Related Considerations

Subgroups:

A. Woman with prior VTE planning pregnancy:

Test for antiphospholipid syndrome (affects obstetric outcomes beyond thrombosis—recurrent miscarriages, preeclampsia, IUGR)
Consider testing for severe inherited deficiencies if result would change prophylaxis strategy

B. Recurrent pregnancy loss (≥3 miscarriages):

Antiphospholipid antibody testing mandatory (not thrombophilia panel)
APS causes 10-15% of recurrent pregnancy loss

C. History of VTE while on OCPs:

Woman now considering resuming hormonal contraception or HRT
Testing for inherited thrombophilia may influence shared decision-making (though estrogen-containing contraceptives generally contraindicated regardless)

The Thrombophilia Tests: What to Order and How to Interpret

The "Focused Panel" Approach

Abandon the reflexive "hypercoagulable panel" checkbox. Instead, order strategically based on clinical scenario.

Clinical Scenario	Initial Tests	Second-Line Tests
Young, unprovoked VTE	Factor V Leiden (genetic), Prothrombin G20210A (genetic), Antiphospholipid antibodies	Protein C, Protein S, Antithrombin (if off anticoagulation x4 weeks)
Recurrent VTE	Antiphospholipid antibodies, CBC with smear, JAK2 V617F	PNH flow cytometry, age-appropriate cancer screening
Splanchnic thrombosis	JAK2 V617F, PNH flow cytometry, Antiphospholipid antibodies	Liver function tests, abdominal imaging for cirrhosis/malignancy
Arterial thrombosis <55 years	Antiphospholipid antibodies, Homocysteine, Lipoprotein(a)	Thrombophilia panel NOT indicated for arterial events
Warfarin skin necrosis	Protein C functional assay (after resolution, off warfarin)	Protein S if Protein C normal

Inherited Thrombophilias: The Big Five

1. Factor V Leiden (FVL) Mutation

Mechanism: G1691A mutation renders Factor V resistant to inactivation by activated Protein C. Result: prolonged thrombin generation.

Prevalence:

Heterozygous: 5% of Caucasians (most common inherited thrombophilia)
Homozygous: 0.02% of Caucasians
Rare in African, Asian, and Indigenous populations

VTE Risk:

Heterozygous: 3-8 fold increased risk (absolute risk ~1%/year)
Homozygous: 50-80 fold increased risk (absolute risk ~5%/year)

Testing:

Genetic test (PCR): Detects G1691A mutation. Can be done anytime (DNA stable).
Functional test (activated Protein C resistance): May be abnormal with pregnancy, OCPs, acute thrombosis. Not recommended.

Management implications:

Heterozygous FVL alone: Does NOT mandate indefinite anticoagulation after first unprovoked VTE. Standard 3-6 months, then reassess bleeding risk.
Homozygous FVL or compound heterozygous (FVL + Prothrombin G20210A): Consider indefinite anticoagulation after first unprovoked proximal VTE.

Pearl: Factor V Leiden is common, but weakly thrombophilic. Don't over-interpret heterozygous results. Most carriers never have VTE.

Pregnancy/OCP counseling:

Heterozygous FVL: Avoid estrogen-containing contraceptives; antepartum/postpartum prophylaxis debated (shared decision-making)
Homozygous FVL or FVL + family history: Prophylactic LMWH during pregnancy recommended

2. Prothrombin G20210A Mutation

Mechanism: G-to-A substitution at position 20210 in 3'-untranslated region of prothrombin gene → elevated prothrombin levels → increased thrombin generation.

Prevalence:

Heterozygous: 2-3% of Caucasians
Homozygous: Very rare

VTE Risk:

Heterozygous: 2-5 fold increased risk
Homozygous: Limited data, likely substantially higher

Testing:

Genetic test (PCR): Detects G20210A mutation. Can be done anytime.
Prothrombin level: Not clinically useful (overlaps with normal range).

Management implications:

Similar to heterozygous Factor V Leiden—weak thrombophilia
Alone, does NOT mandate indefinite anticoagulation
Compound heterozygotes (with FVL) are higher risk

Oyster: Prothrombin G20210A is even weaker than Factor V Leiden. Finding it rarely changes management. Some experts question whether it should be routinely tested.

3. Protein C Deficiency

Mechanism: Protein C is a natural anticoagulant (Vitamin K-dependent). Activated by thrombin-thrombomodulin complex, it inactivates Factors Va and VIIIa. Deficiency → unopposed thrombin generation.

Prevalence:

Heterozygous: 0.2-0.5% of general population
Homozygous/compound heterozygous: Extremely rare, presents with neonatal purpura fulminans (incompatible with life without replacement therapy)

VTE Risk:

Heterozygous: 5-10 fold increased risk

Types:

Type I: Low antigen and activity (quantitative deficiency)
Type II: Normal antigen, low activity (qualitative deficiency)

Testing:

Functional assay (chromogenic): Measures activity. Preferred.
Antigen (immunologic): Measures protein level. Less useful.

Critical timing considerations:

MUST be off warfarin x 2-4 weeks (warfarin depletes Protein C)
Avoid testing during acute thrombosis (consumptive)
Avoid testing during pregnancy (physiologic decrease)
Normal aging decreases levels

Causes of acquired Protein C deficiency:

Warfarin
Vitamin K deficiency
Liver disease (synthesized in liver)
DIC (consumption)
Nephrotic syndrome (urinary loss)

Management implications:

Severe deficiency (<20%): Indefinite anticoagulation after first VTE
Moderate deficiency (20-50%): Consider indefinite anticoagulation after unprovoked VTE
CRITICAL: Use heparin bridge when starting warfarin (risk of warfarin-induced skin necrosis)
DOACs safe (no Protein C depletion phase)

Oyster: Protein C testing is fraught with false positives. If low, repeat off anticoagulation with family cascade testing. Don't make lifelong treatment decisions based on single abnormal value during acute illness.

4. Protein S Deficiency

Mechanism: Protein S is a cofactor for activated Protein C. Deficiency → reduced Protein C anticoagulant activity.

Prevalence:

Heterozygous: 0.03-0.1% (rare)
Homozygous: Extremely rare, severe neonatal thrombosis

VTE Risk:

Heterozygous: 5-10 fold increased risk

Types:

Type I: Low free, total, and activity
Type II: Normal free and total, low activity (rare)
Type III: Low free, normal total, low activity

Testing:

Free Protein S (functional assay): Preferred. Only free Protein S is active (60% bound to C4b-binding protein).
Total Protein S: Less specific.

Critical timing considerations:

MUST be off warfarin x 2-4 weeks
Avoid testing during acute thrombosis
Pregnancy decreases levels (normal in pregnancy can be 25-50% of non-pregnant values)
Estrogen/OCPs decrease levels

Causes of acquired Protein S deficiency:

Warfarin
Pregnancy, OCPs, HRT
Liver disease
Nephrotic syndrome
Acute thrombosis (consumption)
Inflammatory states (C4b-binding protein is acute phase reactant, binds more Protein S)

Management implications:

Similar to Protein C deficiency
Indefinite anticoagulation typically warranted after unprovoked VTE
Use heparin bridge with warfarin initiation

Oyster: Protein S is the most frustrating test. It's affected by EVERYTHING—inflammation, pregnancy, hormones, acute illness, warfarin. False positives are rampant. If isolated low Protein S found, repeat when patient is stable, off anticoagulation, off hormones, and not pregnant before making clinical decisions.

Hack: If you find low Protein S but normal Protein C and Antithrombin in a young woman, ask about OCPs before panicking. Estrogen is the most common cause of "low Protein S" in otherwise healthy patients.

5. Antithrombin Deficiency

Mechanism: Antithrombin is the primary inhibitor of thrombin and Factor Xa. Heparin works by binding to and enhancing Antithrombin activity. Deficiency → severe thrombophilia and heparin resistance.

Prevalence:

Heterozygous: 0.02-0.2% (rare)
Homozygous: Incompatible with life (no reported cases)

VTE Risk:

Heterozygous: 10-50 fold increased risk (HIGHEST of inherited thrombophilias)
Often presents young (<30 years)
High recurrence rate

Types:

Type I: Low antigen and activity (quantitative)
Type II: Normal antigen, low activity (qualitative)

Testing:

Functional assay (chromogenic): Measures activity. Preferred.
Antigen (immunologic): Measures protein level.

Critical timing considerations:

Cannot test on heparin/LMWH (consumption, false low)
Avoid during acute thrombosis
DOACs may interfere with some assays

Causes of acquired Antithrombin deficiency:

Heparin/LMWH therapy (consumption)
DIC (consumption)
Liver disease (decreased synthesis)
Nephrotic syndrome (urinary loss—can be severe, <30%)
L-asparaginase chemotherapy

Management implications:

Indefinite anticoagulation after first VTE—no debate
May require higher LMWH doses or direct thrombin inhibitors (argatroban) in acute setting
Antithrombin concentrate available for acute thrombosis or high-risk procedures
DOACs preferred over warfarin (no monitoring issues, no heparin bridge)

Pearl: Antithrombin deficiency is the most clinically significant inherited thrombophilia. If confirmed, lifelong anticoagulation is non-negotiable. These patients have recurrent VTE despite standard anticoagulation.

Oyster: Nephrotic syndrome can cause profound acquired Antithrombin deficiency (urinary loss of this ~58 kDa protein). Check urinalysis/urine protein-to-creatinine ratio if unexpectedly low Antithrombin in patient with edema.

Summary Table: Inherited Thrombophilias

Defect	Prevalence (Caucasians)	VTE Risk Increase	Test Timing	Management After 1st Unprovoked VTE
Factor V Leiden (heterozygous)	5%	3-8x	Anytime (genetic)	3-6 months, reassess
Factor V Leiden (homozygous)	0.02%	50-80x	Anytime (genetic)	Indefinite
Prothrombin G20210A	2-3%	2-5x	Anytime (genetic)	3-6 months, reassess
Protein C deficiency	0.2-0.5%	5-10x	Off warfarin x4 weeks	Indefinite (if severe)
Protein S deficiency	0.03-0.1%	5-10x	Off warfarin x4 weeks	Indefinite (if severe)
Antithrombin deficiency	0.02-0.2%	10-50x	Off heparin	Indefinite (always)

Acquired Thrombophilias: The High-Yield Diagnoses

These are MORE important than inherited thrombophilias in adults with recurrent VTE because:

They're more common in adult-onset thrombosis
They require specific therapies beyond standard anticoagulation
They have systemic manifestations beyond thrombosis

Antiphospholipid Syndrome (APS): The Triple Positivity and Warfarin Monotherapy

Clinical Presentation

Antiphospholipid syndrome is the MOST important acquired thrombophilia. It accounts for 10-15% of first VTE and up to 20% of recurrent VTE.

Diagnostic Criteria (Revised Sapporo Criteria):

Clinical Criteria (≥1 required):

Vascular thrombosis: Arterial OR venous OR small vessel, in any tissue/organ, confirmed by imaging or histology
Pregnancy morbidity:
- ≥1 unexplained fetal death (≥10 weeks gestation), normal morphology
- ≥1 premature birth (<34 weeks) due to severe preeclampsia, eclampsia, or placental insufficiency
- ≥3 consecutive spontaneous abortions (<10 weeks), excluding anatomic/hormonal/chromosomal causes

Laboratory Criteria (≥1 required, on ≥2 occasions, ≥12 weeks apart):

Lupus anticoagulant (LA) positive
Anticardiolipin antibodies (aCL) IgG or IgM, medium-to-high titer (>40 GPL/MPL or >99th percentile)
Anti-β2-glycoprotein-I antibodies (anti-β2GPI) IgG or IgM, medium-to-high titer (>99th percentile)

Definite APS: ≥1 clinical + ≥1 laboratory criterion

Pearl: The 12-week confirmation requirement is CRITICAL. Transient positive antibodies occur with infections, medications, and acute illnesses. Don't diagnose APS based on single positive test.

Clinical Phenotypes

Classic Presentation:

Woman in 30s-40s
History of recurrent miscarriages AND/OR thrombosis
Positive lupus anticoagulant
May have underlying SLE (20-30% of APS patients) or "primary" APS (70-80%)

Oyster: APS causes both arterial AND venous thrombosis. If a young patient has DVT AND stroke, think APS. No other common thrombophilia crosses the arterial-venous divide.

"Triple-Positive" APS:

All three antibodies positive (LA + aCL + anti-β2GPI)
Highest thrombotic risk (~5%/year)
Highest pregnancy loss risk
Highest risk for catastrophic APS

Catastrophic APS (CAPS):

Rare (<1% of APS patients), life-threatening
Acute multi-organ thrombosis (typically small vessels)
Precipitated by infection, surgery, anticoagulation withdrawal, malignancy
Triad: Thrombosis in ≥3 organs + evidence of microangiopathy + positive aPL antibodies
Mortality 30-50% despite treatment

Treatment of CAPS:

Therapeutic anticoagulation (heparin)
High-dose corticosteroids
IVIG (0.4 g/kg daily x 5 days)
Plasma exchange
Rituximab in refractory cases
Treat precipitating factor aggressively

Laboratory Testing: The Nuances

When to Test:

Any patient with venous thrombosis age <50, especially if unprovoked
Any patient with arterial thrombosis age <55
Recurrent VTE
VTE in unusual sites
Recurrent pregnancy loss (≥3 consecutive miscarriages)
Thrombocytopenia + thrombosis
Unexplained splenomegaly
Thrombosis despite "normal" CBC (occult MPN presents with normal counts in 10-15%)

Pearl: In ANY patient with splanchnic vein thrombosis, order JAK2 V617F mutation testing immediately. Pretest probability is 30-40%, and diagnosis changes management.

The JAK2 V617F Mutation

Mechanism: Gain-of-function mutation in JAK2 (Janus Kinase 2) gene causes constitutive activation of JAK-STAT pathway → uncontrolled proliferation of myeloid lineages.

Prevalence in MPNs:

Polycythemia Vera: 95-97%
Essential Thrombocythemia: 50-60%
Primary Myelofibrosis: 50-60%

Testing:

JAK2 V617F mutation (PCR): Simple blood test, can be done anytime
Quantitative (allele burden): >50% suggests PV, lower burdens in ET/PMF
JAK2 exon 12 mutations: Test if high clinical suspicion for PV but V617F negative (rare, 3% of PV)

Diagnostic Criteria for PV and ET

Polycythemia Vera (2016 WHO Criteria):

Major Criteria:

Hemoglobin >16.5 g/dL (men) or >16 g/dL (women), OR Hematocrit >49% (men) or >48% (women), OR increased red cell mass
Bone marrow biopsy: Hypercellularity with trilineage growth, prominent erythroid/granulocytic/megakaryocytic proliferation
JAK2 V617F or JAK2 exon 12 mutation

Minor Criterion:

Subnormal serum erythropoietin (EPO) level

Diagnosis: All 3 major criteria OR first 2 major + minor criterion

Pearl: Low EPO is KEY to distinguishing PV from secondary erythrocytosis (sleep apnea, COPD, smoking, renal tumors produce EPO → high levels).

Essential Thrombocythemia (2016 WHO Criteria):

Major Criteria:

Platelet count ≥450,000/μL
Bone marrow biopsy: Proliferation of megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no increase in granulopoiesis or erythropoiesis
Not meeting WHO criteria for PV, PMF, CML, MDS, or other myeloid neoplasm
JAK2 V617F, CALR, or MPL mutation

Minor Criterion:

Presence of clonal marker OR absence of evidence for reactive thrombocytosis

Diagnosis: All 4 major criteria OR first 3 major + minor criterion

Hack: If JAK2 V617F negative in suspected ET, order CALR (calreticulin) and MPL (thrombopoietin receptor) mutations. Together, these three mutations account for 90% of ET cases.

Oyster: ~10% of ET is "triple-negative" (JAK2/CALR/MPL all negative). These patients have LOWER thrombotic risk. If triple-negative with platelets <1,000,000, antiplatelet alone may suffice.

Thrombotic Risk Stratification in MPN

Polycythemia Vera:

Risk Category	Criteria	Annual Thrombosis Risk	Management
Low	Age <60 AND no thrombosis history	2%/year	Phlebotomy to Hct <45%, aspirin 81 mg daily
High	Age ≥60 OR thrombosis history	5-7%/year	Phlebotomy + aspirin + cytoreduction (hydroxyurea)

Essential Thrombocythemia:

Risk Category	Criteria	Management
Very low	Age <60, JAK2-negative, no thrombosis history	Observation OR aspirin (controversial)
Low	Age <60, JAK2-positive, no thrombosis history	Aspirin 81 mg daily
Intermediate	Age 60-70, no thrombosis history	Aspirin ± cytoreduction (individualized)
High	Age >70 OR thrombosis history	Aspirin + cytoreduction (hydroxyurea)

Pearl: In PV, the target hematocrit is <45% (CYTO-PV trial showed doubling of thrombosis rate with Hct 45-50% vs <45%). Phlebotomy every 1-4 weeks as needed.

Management of Thrombosis in MPN

Acute VTE/Arterial Thrombosis:

Standard anticoagulation (therapeutic dose LMWH or heparin, transition to warfarin or DOAC)
Aspirin 81 mg daily (in addition to anticoagulation)—reduces microvascular thrombosis
Consider cytoreduction even if not previously indicated

Chronic Management:

Indefinite anticoagulation after first thrombotic event (recurrence risk 10-15%/year off anticoagulation)
Aspirin indefinitely (proven to reduce thrombosis in PV/ET by 50-60% in primary prevention trials)
Cytoreduction (hydroxyurea first-line):
- Target platelets <400,000 in ET
- Target Hct <45% in PV (with phlebotomy)
- Consider interferon-α in young patients/pregnancy

Splanchnic Vein Thrombosis:

Anticoagulation (warfarin or DOAC, indefinite duration)
Cytoreduction (hydroxyurea)
Monitor for portal hypertension complications (varices, ascites)

Oyster: Don't withhold aspirin due to thrombocytosis. The thrombocytosis in ET/PV is PRO-thrombotic, not anti-thrombotic. Paradoxically, very high platelets (>1,000,000) can cause acquired von Willebrand deficiency and bleeding—treat with cytoreduction, not aspirin avoidance.

Hack: If patient with known MPN develops acute thrombosis and platelet count is extremely elevated (>800,000), consider plateletpheresis as emergency cytoreduction while waiting for hydroxyurea to work (takes 1-2 weeks).

Pregnancy in MPN:

High-risk pregnancy (thrombosis, hemorrhage, pregnancy loss)
Stop hydroxyurea (teratogenic)
Switch to interferon-α (pregnancy category C, but safest cytoreductive agent)
LMWH prophylaxis or therapeutic dose (if history of thrombosis)
Low-dose aspirin (81 mg)
Close maternal-fetal medicine follow-up

Paroxysmal Nocturnal Hemoglobinuria (PNH): The Intravascular Hemolysis Clue

PNH is rare (1-2 per million) but MUST be considered in specific clinical contexts because:

It causes life-threatening thromboses in unusual sites
It's easily diagnosed with flow cytometry
It's treatable with targeted therapy (eculizumab)

Pathophysiology

Mechanism: Acquired mutation in PIGA gene (X-linked, somatic) in hematopoietic stem cell → deficiency of GPI-anchored proteins, including:

CD55 (decay-accelerating factor): Protects cells from complement
CD59 (membrane inhibitor of reactive lysis): Protects cells from complement

Result: Red cells lysed by complement → intravascular hemolysis, hemoglobinuria, thrombosis

Why thrombosis? Free hemoglobin scavenges nitric oxide → endothelial dysfunction, platelet activation. Inflammatory microparticles from hemolyzed cells activate coagulation.

Clinical Clues for PNH

Classic Triad:

Intravascular hemolysis (hemoglobinuria, elevated LDH, low haptoglobin, reticulocytosis)
Cytopenias (often bone marrow failure—aplastic anemia overlap)
Thrombosis (venous, especially splanchnic)

When to suspect:

Thrombosis in unusual sites:

Hepatic vein thrombosis (Budd-Chiari syndrome): PNH present in 10-20%
Portal, mesenteric, splenic vein thrombosis
Cerebral venous sinus thrombosis
Dermatomal skin infarction (rare but pathognomonic)

Hemolytic anemia with:

Disproportionately elevated LDH (>2-3x ULN with only moderate anemia)
Hemoglobinuria (dark urine, especially morning—"paroxysmal nocturnal")
Low/undetectable haptoglobin
Negative Coombs test (rules out autoimmune hemolysis)

Aplastic anemia with:

Cytopenias + hemolysis (30% of aplastic anemia patients have PNH clone)
Disproportionate symptoms (fatigue, dyspnea) relative to degree of anemia

Pearl: Not all PNH patients have nocturnal hemoglobinuria. Classic "morning dark urine" occurs in <50%. Don't let absence of hemoglobinuria dissuade you from testing if other features present.

Oyster: LDH >1,000 U/L with negative Coombs test = PNH until proven otherwise. This is intravascular hemolysis, not immune-mediated.

Diagnostic Testing

Screening Test: Flow Cytometry for GPI-Anchored Proteins

Technique:

Peripheral blood sample (EDTA tube)
Flow cytometry measures CD55/CD59 on red cells, granulocytes, monocytes
Reports percentage of cells deficient in GPI-anchored proteins (PNH clone size)

Interpretation:

Normal: <1% PNH cells
Small clone: 1-10% (may be clinically silent, monitor)
PNH: >10% on granulocytes or monocytes (diagnostic)
Classic PNH: >50% PNH granulocytes + hemolysis/thrombosis

Pearl: Test GRANULOCYTES and MONOCYTES, not just RBCs. RBCs have shorter lifespan—transfusions dilute PNH RBCs. WBCs give more stable assessment of clone size.

Additional Testing:

CBC with reticulocyte count: Anemia, thrombocytopenia (often), reticulocytosis (if marrow intact)
LDH: Markedly elevated (intravascular hemolysis marker)
Haptoglobin: Undetectable (binds free hemoglobin)
Indirect bilirubin: Elevated (hemoglobin breakdown)
Coombs test: Negative (excludes autoimmune hemolysis)
Urinalysis: Hemoglobinuria (no RBCs on microscopy—free hemoglobin, not intact cells)
Bone marrow biopsy: If cytopenias—assess for aplastic anemia overlap

Oyster: PNH and aplastic anemia are "cousins." 30% of aplastic anemia evolves into PNH, 25% of PNH has hypoplastic marrow. Screen aplastic anemia patients for PNH routinely.

Thrombotic Risk and Management

Thrombotic Risk:

40% of PNH patients experience thrombosis (most common cause of death)
Risk correlates with clone size: >50% granulocytes = very high risk
Splanchnic veins (portal, hepatic, mesenteric) most common—"Why does thrombosis go to the gut?" Unclear, possibly local complement activation

Management of PNH:

1. Complement Inhibition (C5 inhibitors)—FIRST-LINE for Hemolysis/Thrombosis:

Eculizumab (Soliris):

Monoclonal antibody against complement C5
Prevents terminal complement activation (membrane attack complex formation)
Dramatically reduces hemolysis (LDH normalizes, transfusion-independence in 50%)
Reduces thrombosis risk by ~90%

Dosing:

Induction: 600 mg IV weekly x 4 weeks, then 900 mg week 5
Maintenance: 900 mg IV every 2 weeks indefinitely

Indications:

Symptomatic hemolysis with transfusion dependence
History of thrombosis
Large PNH clone (>50%) with elevated LDH even if asymptomatic

CRITICAL Safety Concern: Meningococcal Infection

Eculizumab increases risk of invasive Neisseria meningitidis infection 1,000-2,000 fold
MUST vaccinate ≥2 weeks before starting (quadrivalent meningococcal vaccine + serogroup B vaccine)
Antibiotic prophylaxis (penicillin or macrolide) until 2 weeks post-vaccination
Patients should carry emergency antibiotics

Newer agent: Ravulizumab (Ultomiris):

Long-acting C5 inhibitor, same efficacy as eculizumab
Dosed every 8 weeks (more convenient)

Pearl: Eculizumab doesn't cure PNH (clone persists), but it prevents complications. Treat indefinitely.

2. Anticoagulation:

Primary prophylaxis (no prior thrombosis):

Controversial. No RCT data.
Consider in:
- Large clone (>50%)
- Elevated D-dimer
- Not on eculizumab (or breakthrough hemolysis on eculizumab)
Options: Warfarin (INR 2-3) or DOAC (apixaban, rivaroxaban)

Secondary prophylaxis (history of thrombosis):

Indefinite anticoagulation (very high recurrence risk)
Warfarin (INR 2-3) OR DOAC
Continue even if on eculizumab (drug reduces but doesn't eliminate thrombosis risk)

Oyster: Some experts advocate for anticoagulation in ALL PNH patients with large clones and active hemolysis. Thrombosis is the leading cause of death—prevention is paramount.

Hack: If patient with known PNH develops acute thrombosis and is NOT on eculizumab, start complement inhibitor URGENTLY (within 24-48 hours if possible). This addresses the underlying pathophysiology, not just the clot.

3. Supportive Care:

Folic acid 1 mg daily (increased RBC turnover)
Iron supplementation (chronic hemoglobinuria → urinary iron loss)
Transfusion support (washed or leukoreduced RBCs to minimize transfusion reactions)
Bone marrow transplant: Only curative therapy, reserved for severe aplastic anemia component or refractory disease

Trousseau's Syndrome of Malignancy: Recurrent, Migratory Thromboses

Historical Context and Modern Understanding

In 1865, Armand Trousseau described "migratory thrombophlebitis" in cancer patients—and diagnosed his own gastric cancer based on his recurrent DVTs. He died 18 months later.

Trousseau's Syndrome: Cancer-associated thrombosis, classically:

Recurrent thromboses
Migratory (different sites)
Resistant to anticoagulation
Superficial or deep veins, or arterial

Modern Definition (broader): Any VTE in setting of active malignancy.

Epidemiology:

Cancer increases VTE risk 4-7 fold
20% of "unprovoked" VTE has occult cancer diagnosed within 1 year
VTE is 2nd leading cause of death in cancer patients (after cancer progression)
Certain cancers are highest risk: pancreas, brain, lung, ovary, gastric, hematologic

Pathophysiology: Why Cancer Causes Thrombosis

Mechanisms (multifactorial):

Tumor procoagulants:
- Tissue factor (TF): Expressed on tumor cells, microparticles → activates Factor VII → thrombin generation
- Cancer procoagulant: Cysteine protease that directly activates Factor X (independent of Factor VII)
Inflammatory cytokines:
- IL-1, IL-6, TNF-α → upregulate endothelial TF, downregulate thrombomodulin
Platelet activation:
- Tumor cells activate platelets → aggregation, release of procoagulant microparticles
Stasis and compression:
- Tumor mass compresses veins (pelvic, abdominal tumors)
- Immobility from cancer cachexia, pain
Treatment-related:
- Chemotherapy (cisplatin, L-asparaginase, thalidomide/lenalidomide + dexamethasone)
- Central venous catheters
- Surgery

Clinical Clues for Occult Malignancy

When to suspect cancer-associated VTE:

"Unprovoked" VTE with red flags:

Age >50
Extensive thrombosis (bilateral, or extending to IVC/iliac veins)
Recurrent VTE despite adequate anticoagulation
Splanchnic vein thrombosis (pancreatic cancer)
Migratory superficial thrombophlebitis (pancreatic, lung)
Constitutional symptoms (weight loss, night sweats, anorexia)
Abnormal labs: Anemia, thrombocytosis, elevated platelets, elevated D-dimer (>6x ULN)

Classic Trousseau's presentation:

Migratory superficial thrombophlebitis (tender, cord-like superficial veins, changing locations)
Resistant to anticoagulation (new thromboses despite therapeutic INR/anti-Xa)
Often adenocarcinomas: pancreas (25%), lung (15%), GI (10%), prostate, breast, ovary

Pearl: Unprovoked bilateral DVTs or recurrent VTE at different sites within weeks should prompt aggressive cancer screening.

Oyster: Superficial thrombophlebitis in non-varicose veins is NOT benign. Migratory superficial thrombophlebitis has 50% association with visceral malignancy—scan these patients.

Cancer Screening After Unprovoked VTE

Controversial Question: How extensively should we screen for occult cancer after unprovoked VTE?

Two Approaches:

1. "Limited Screening" (Most Guidelines):

Comprehensive history and physical exam
Basic labs: CBC, CMP, LFTs
Age-appropriate cancer screening (colonoscopy if due, mammography, Pap smear)
CT chest/abdomen/pelvis if:
- Constitutional symptoms
- Abnormal labs
- Recurrent VTE
- Age >50 with extensive thrombosis

Evidence: SOMIT trial (2015) showed extensive screening (CT CAP + tumor markers) diagnosed more cancers but did NOT improve cancer-related mortality or overall survival.

2. "Extensive Screening":

CT chest/abdomen/pelvis for ALL unprovoked VTE
Tumor markers (CEA, CA 19-9, CA-125, PSA)
Consider PET-CT in high-risk patients

Current Consensus (ASCO, ISTH Guidelines):

Routine extensive screening NOT recommended for all unprovoked VTE
Clinical judgment-based screening for patients with high-risk features

Oyster: Unprovoked VTE increases cancer risk, but only 4-5% will have cancer diagnosed in the next year. Overtesting leads to false positives, incidental findings, anxiety, and cost without clear mortality benefit.

Hack: Use the Ottawa Score to risk-stratify:

Variable	Points
Male sex	+1
Age ≥51-60 years	+1
Age ≥61-70 years	+2
Age >70 years	+3
Prior VTE	+1
Abnormal hemoglobin (<80 or >130 g/L in women, <90 or >170 g/L in men)	+2
Abnormal WBC (>11 x 10⁹/L)	+2
Abnormal platelets (<150 or >350 x 10⁹/L)	+2

Score ≥3: Consider CT chest/abdomen/pelvis (cancer prevalence ~10%) Score <3: Age-appropriate screening only

Management of Cancer-Associated VTE

Acute Treatment:

LMWH or fondaparinux preferred over UFH (ease of dosing, outpatient)
DOACs emerging as alternative (see below)

Chronic Anticoagulation:

FIRST-LINE: Low Molecular Weight Heparin (LMWH)

Evidence:

CLOT trial (2003): Dalteparin vs warfarin → 50% reduction in recurrent VTE with LMWH
CATCH trial (2015): Tinzaparin vs warfarin → similar results

Dosing:

Dalteparin: 200 units/kg SC daily x 1 month, then 150 units/kg daily
Enoxaparin: 1 mg/kg SC q12h OR 1.5 mg/kg daily
Tinzaparin: 175 units/kg SC daily

Duration: Indefinite, or until cancer cured/remission AND ≥6 months anticoagulation

Advantages of LMWH:

Superior efficacy vs warfarin in cancer
No dietary interactions
No frequent monitoring (unlike warfarin)
Less drug-drug interactions with chemotherapy

Disadvantages:

Daily injections (patient burden)
Cost (not always covered)
Renal dosing required (CrCl <30)

SECOND-LINE: Direct Oral Anticoagulants (DOACs)

Evidence:

SELECT-D trial (2018): Rivaroxaban vs dalteparin → fewer recurrent VTE (4% vs 11%), BUT more bleeding (6% vs 4%), especially GI cancers
Hokusai-VTE Cancer trial (2018): Edoxaban vs dalteparin → non-inferior for VTE, more bleeding with edoxaban (especially GI cancers)
CARAVAGGIO trial (2020): Apixaban vs dalteparin → non-inferior for VTE AND bleeding (breakthrough result)

Current Recommendations (ASCO, ITAC, ISTH):

DOACs acceptable alternative to LMWH in select patients
Apixaban or rivaroxaban preferred (most data, apixaban has best bleeding profile)
Avoid DOACs in:
- Luminal GI cancers (esophageal, gastric, colorectal)—high bleeding risk
- Genitourinary cancers (renal, bladder)—high bleeding risk
- Drug-drug interactions with chemotherapy (certain tyrosine kinase inhibitors)
- Patients with prior major GI bleed

Dosing:

Apixaban: 10 mg PO BID x 7 days, then 5 mg BID
Rivaroxaban: 15 mg PO BID x 21 days, then 20 mg daily
Edoxaban: Enoxaparin 1 mg/kg BID x 5 days, then edoxaban 60 mg daily

Pearl: DOACs have revolutionized cancer-associated VTE management. Patients overwhelmingly prefer oral therapy to daily injections. Shared decision-making is key.

Oyster: If GI cancer + VTE, strongly favor LMWH over DOAC. The bleeding risk is real—SELECT-D showed 13% major bleeding in GI cancers on rivaroxaban.

THIRD-LINE: Warfarin

Inferior to LMWH
Only use if LMWH/DOAC contraindicated or unavailable
Target INR 2-3
Frequent INR monitoring (cancer, chemotherapy, malnutrition → INR fluctuations)

Management of Recurrent VTE Despite Anticoagulation:

"Anticoagulation failure" = new VTE despite therapeutic anticoagulation

Approach:

Confirm compliance and therapeutic levels:
- LMWH: Check anti-Xa level (peak 4 hours post-dose, target 0.6-1.0 for BID dosing, 1.0-2.0 for daily dosing)
- Warfarin: Confirm INR 2-3
- DOAC: Check trough level (interpretive challenges)
If subtherapeutic, optimize dosing:
- LMWH: Increase dose by 20-25%
- Warfarin: Increase target INR to 2.5-3.5
- DOAC: Unclear; consider switch to LMWH
If therapeutic, escalate:
- Switch from DOAC/warfarin to LMWH (if not already on it)
- Increase LMWH dose (e.g., dalteparin 200 units/kg daily instead of 150)
- Consider IVC filter (controversial, temporary retrievable filter only)

Pearl: Don't reflexively place IVC filters in cancer patients. They have high thrombotic burden—filters often thrombose. Filter should be LAST resort, temporary, with plan for removal.

Incidental Pulmonary Embolism (PE):

Asymptomatic PE found on CT scan obtained for cancer staging/surveillance
Treat same as symptomatic PE (anticoagulation indefinite)
NOT benign—10% mortality in first year if untreated

Catheter-Associated Thrombosis:

Upper extremity DVT related to central venous catheter (port, PICC, tunneled catheter)
Anticoagulation (LMWH or DOAC) if symptomatic or extending beyond catheter tip
Do NOT remove functional catheter unless infected or malfunctioning
Anticoagulate for ≥3 months or until catheter removed + 4 weeks

Putting It All Together: The Diagnostic Algorithm

Recurrent or Unusual VTE
↓
STEP 1: Determine if testing indicated
- Young (<50), unprovoked
- Recurrent (≥2 events)
- Unusual site (splanchnic, cerebral)
- Strong family history
- Pregnancy considerations
↓ YES
STEP 2: Clinical phenotyping
↓
├── Arterial + Venous thrombosis? → Test for APS
├── Splanchnic vein thrombosis? → JAK2, PNH flow cytometry
├── Hemolysis (high LDH, low haptoglobin)? → PNH flow cytometry
├── Thrombocytosis? → JAK2, CBC/smear
├── Migratory superficial thrombophlebitis? → Cancer screening
├── Constitutional symptoms? → Cancer screening
└── None of above → Consider inherited thrombophilia
↓
STEP 3: Order TARGETED tests (not "shotgun panel")
↓
Acquired thrombophilias (higher yield in adults):
- Antiphospholipid antibodies (LA, aCL, anti-β2GPI)
- JAK2 V617F mutation
- PNH flow cytometry (CD55/CD59)
- Age-appropriate cancer screening
↓
Inherited thrombophilias (if age <50, unprovoked, or strong family history):
- Factor V Leiden (genetic)
- Prothrombin G20210A (genetic)
- Protein C, Protein S, Antithrombin (off anticoagulation x4 weeks)
↓
STEP 4: Interpret results in clinical context
- Single abnormal test → Repeat for confirmation
- Low-titer aPL antibodies → Clinical significance unclear
- Heterozygous FVL/Prothrombin → Weak thrombophilia, may not change management
- Antithrombin deficiency or triple-positive APS → Definite indefinite anticoagulation
↓
STEP 5: Individualized management based on:
- Bleeding risk (HAS-BLED score)
- Thrombosis burden and site
- Patient preference
- Specific thrombophilia identified

Clinical Pearls and Hacks: Summary Box

Testing Strategy Pearls

Don't test everyone: Only test if results will change management or provide actionable information for patient/family.
Timing matters: Protein C, S, Antithrombin falsely low during acute thrombosis, on warfarin, or on heparin. Wait ≥4 weeks off anticoagulation. Genetic tests (FVL, Prothrombin) can be done anytime.
Confirm before committing: Single abnormal result ≠ diagnosis. Repeat testing mandatory, especially for aPL antibodies (12 weeks) and protein deficiencies.
Acquired > Inherited in adults: Focus on APS, MPN, PNH, and malignancy in adult-onset thrombosis. Inherited thrombophilias are more relevant in pediatric/young adult patients.
Family cascade testing: If severe inherited deficiency confirmed (Protein C/S/Antithrombin <30%, homozygous FVL), offer testing to first-degree relatives. Heterozygous FVL alone doesn't warrant family screening.

Diagnosis Hacks

The "Splanchnic Triad": Splanchnic vein thrombosis → order JAK2, PNH flow, and APS panel. These three account for 60-70% of identifiable causes.
LDH is your friend: Markedly elevated LDH (>1,000) with anemia + low haptoglobin + negative Coombs = PNH until proven otherwise.
Triple-positive = high risk: All three aPL antibodies positive (LA + aCL + anti-β2GPI) = highest thrombotic risk. These patients MUST be on warfarin, NOT DOACs.
Don't forget the simple stuff: Prolonged aPTT in young patient with thrombosis? Check for lupus anticoagulant before assuming factor deficiency or heparin contamination.
Thrombocytosis with thrombosis = MPN until proven otherwise: Elevated platelets (>450,000) + VTE in patient <60 years = order JAK2 immediately.

Management Hacks

APS + venous thrombosis = warfarin INR 2-3: NOT higher. WAPS trial showed no benefit of INR 3-4 and increased bleeding.
APS + arterial thrombosis = warfarin + aspirin: Dual therapy for arterial events or recurrence on warfarin alone.
PV hematocrit target <45%: CYTO-PV trial definitive—Hct 45-50% doubles thrombotic risk. Phlebotomize aggressively.
Cancer-associated VTE = LMWH or DOAC, indefinitely: LMWH superior to warfarin. Apixaban acceptable alternative except in GI/GU cancers.
Eculizumab requires meningococcal vaccination: C5 inhibitor therapy without vaccination = Russian roulette with Neisseria meningitidis. Vaccinate ≥2 weeks before starting.

Pregnancy Pearls

Test for APS in recurrent pregnancy loss: 10-15% of recurrent miscarriages due to APS. LMWH + aspirin reduces loss from 90% to 30%.
Warfarin is teratogenic: Switch to LMWH before conception or as soon as pregnancy confirmed. Warfarin causes fetal warfarin syndrome (nasal hypoplasia, stippled epiphyses) in first trimester, CNS abnormalities in second/third trimester.
VTE in pregnancy + thrombophilia = prophylaxis for life: Not just during pregnancy. Counsel about future pregnancy risk and postpartum period (highest thrombotic risk).

Communication Pearls

Explain the "why" of testing: "We're checking to see if there's an underlying condition causing your blood clots that would require long-term treatment or affect your family members."
Manage expectations about "answers": "Even with comprehensive testing, we may not find a specific cause. That doesn't mean there isn't one—we just don't have tests for every factor yet."
Frame indefinite anticoagulation positively: "This medication protects you from future life-threatening clots. Think of it like taking medication for high blood pressure—preventing something worse."
Counsel about modifiable risks: Even with thrombophilia, long flights, oral contraceptives, smoking, and prolonged immobility dramatically increase risk. Address these proactively.

Safety Pearls

Never diagnose based on single test: Especially for aPL antibodies and protein deficiencies. Transient positives are common with infections, inflammation, medications.
Document shared decision-making: If patient with weak thrombophilia (heterozygous FVL) chooses indefinite anticoagulation despite standard recommendation for finite treatment, document discussion, risks/benefits, bleeding risk assessment.
Bridge warfarin in known/suspected Protein C deficiency: Overlap heparin/LMWH for ≥5 days AND until INR therapeutic x 2 consecutive days to prevent warfarin-induced skin necrosis.
Review medications for drug interactions: Many chemotherapy agents, antibiotics (rifampin), and antiepileptics affect warfarin metabolism. DOACs have fewer but important interactions (strong CYP3A4/P-gp inhibitors).

Special Populations and Scenarios

Pregnancy and Thrombophilia: Navigating the Risks

Pregnancy is inherently prothrombotic (5-10 fold increased VTE risk), peaking in the postpartum period. Thrombophilia further amplifies this risk.

Thromboprophylaxis Strategies

Thrombophilia	No Prior VTE	Prior VTE (Not on Estrogen)	Prior VTE (On Estrogen)
None	Surveillance OR prophylactic LMWH if additional risk factors	Prophylactic or intermediate-dose LMWH antepartum, therapeutic postpartum x6 weeks	Intermediate-dose LMWH antepartum, therapeutic postpartum
Low-risk (heterozygous FVL or Prothrombin)	Surveillance OR prophylactic LMWH if family history of VTE	Prophylactic or intermediate-dose LMWH antepartum, therapeutic postpartum	Therapeutic LMWH throughout pregnancy + postpartum
High-risk (homozygous FVL, compound heterozygote, Protein C/S/AT deficiency)	Prophylactic LMWH antepartum, therapeutic postpartum x6 weeks	Therapeutic LMWH throughout pregnancy + postpartum x6 weeks	Therapeutic LMWH throughout pregnancy + postpartum
Antiphospholipid syndrome	Prophylactic LMWH + aspirin 81 mg (if obstetric APS only)	Therapeutic LMWH + aspirin 81 mg throughout	Therapeutic LMWH + aspirin 81 mg throughout

LMWH Dosing in Pregnancy:

Prophylactic: Enoxaparin 40 mg SC daily OR dalteparin 5,000 units SC daily
Intermediate: Enoxaparin 40 mg SC q12h OR dalteparin 5,000 units SC q12h
Therapeutic: Enoxaparin 1 mg/kg SC q12h OR dalteparin 200 units/kg SC daily (adjust for weight gain throughout pregnancy)

Pearl: Dosing adjustments needed as pregnancy progresses due to increased renal clearance and volume of distribution. Monitor anti-Xa levels in third trimester if on therapeutic dosing (target peak 0.6-1.0 for BID dosing).

Neuraxial Anesthesia Timing

CRITICAL for labor planning:

Prophylactic-dose LMWH:

Last dose ≥12 hours before epidural/spinal
Can restart 4 hours after catheter removal

Therapeutic-dose LMWH:

Last dose ≥24 hours before epidural/spinal
Can restart 4 hours after catheter removal

Pearl: Coordinate with obstetrics and anesthesia early (third trimester). If spontaneous labor, may need to avoid neuraxial anesthesia or use alternative pain management.

Postpartum Management

Duration:

Minimum 6 weeks postpartum (highest VTE risk period)
Can transition to warfarin (safe with breastfeeding) OR continue LMWH OR use DOAC (avoid if breastfeeding—limited data)

Contraception counseling:

Avoid estrogen-containing contraceptives (OCPs, patch, ring) indefinitely
Safe options: Progestin-only pill, IUD (hormonal or copper), depot medroxyprogesterone, barrier methods

Pediatric Thrombosis: When to Suspect Inherited Thrombophilia

Pediatric VTE is rare (0.07-0.14 per 10,000 children) and usually provoked by:

Central venous catheters (50-60% of pediatric VTE)
Malignancy/chemotherapy
Congenital heart disease
Infection/sepsis
Trauma

When to test children:

Unprovoked VTE (no identifiable risk factor)
Recurrent VTE
Neonatal purpura fulminans (homozygous Protein C/S deficiency)
Strong family history (multiple relatives, young age at presentation)
Unusual site thrombosis (cerebral, splanchnic)

Testing approach:

Genetic tests first (FVL, Prothrombin)—can be done anytime
Defer protein testing until older (>6 months) and off anticoagulation—levels change with age and development

Management:

Minimum 3 months anticoagulation (same as adults)
Indefinite anticoagulation only if: recurrent VTE, severe deficiency (AT, homozygous FVL), or life-threatening thrombosis

Pearl: Many pediatric VTE events are catheter-related. Remove catheter if feasible (infection, malfunction, no longer needed) and anticoagulate for 6 weeks to 3 months.

Thrombophilia and Oral Contraceptives: Quantifying the Risk

Estrogen-containing contraceptives increase VTE risk 3-6 fold (varies by formulation, estrogen dose, progestin type).

Absolute Risk in General Population:

No OCP: 1-2 per 10,000 women-years
On OCP: 6-12 per 10,000 women-years

Risk with Thrombophilia + OCP:

Thrombophilia	Baseline VTE Risk (per 10,000 women-years)	Risk on OCP (per 10,000 women-years)	Absolute Risk Increase
None	1-2	6-12	+5-10
Heterozygous FVL	5-10	30-60	+25-50
Prothrombin G20210A	4-8	20-40	+16-32
Protein C deficiency	10-20	50-100	+40-80
Antithrombin deficiency	20-40	100-200	+80-160

Clinical Implications:

Known thrombophilia: Avoid estrogen-containing contraceptives. Use progestin-only methods, IUD, or barrier methods.
Family history of VTE in first-degree relative <50 years: Consider testing for thrombophilia before prescribing OCPs (controversial—some guidelines recommend, others don't).
VTE on OCPs: Stop OCPs immediately, anticoagulate for ≥3 months. Test for thrombophilia off anticoagulation if considering future hormonal contraception (though generally avoided).

Oyster: Routine thrombophilia screening before prescribing OCPs to healthy women is NOT recommended—low yield, high false-positive rate, and finding heterozygous FVL wouldn't prohibit use in some guidelines (individualized decision-making).

Hack: Progestin-only pills, depot medroxyprogesterone, IUDs (hormonal/copper), and implants do NOT increase VTE risk and are safe alternatives in women with thrombophilia.

Thrombophilia and Air Travel: Evidence-Based Recommendations

Long-distance air travel (>4-6 hours) increases VTE risk 2-4 fold due to prolonged immobility, dehydration, and hypoxia.

Risk by Thrombophilia Status:

Category	Baseline Risk per Flight	Recommendations
No thrombophilia, no prior VTE	1 in 6,000	Hydration, ambulation q2h, calf exercises
Thrombophilia, no prior VTE	1 in 2,000	Above + compression stockings OR prophylactic LMWH (single dose pre-flight)
Prior VTE, on anticoagulation	Low (if therapeutic)	Continue anticoagulation, hydration, ambulation
Prior VTE, off anticoagulation	1 in 500-1,000	Prophylactic LMWH (enoxaparin 40 mg SC 2-4 hours pre-flight) + compression stockings
High-risk thrombophilia (AT deficiency, recurrent VTE)	1 in 200-500	Prophylactic LMWH + compression stockings, consider resuming long-term anticoagulation

Pearl: Compression stockings alone reduce VTE risk by ~60% in air travel. Knee-high graduated compression (15-30 mmHg) sufficient—full-length not necessary.

Oyster: Aspirin is NOT effective for VTE prevention in air travel. LOFT trial (2012) showed no benefit. If pharmacologic prophylaxis warranted, use LMWH.

Emerging Therapies and Future Directions

Factor XI Inhibitors: The Next Generation

Rationale: Factor XI plays a role in thrombosis but minimal role in hemostasis. Deficiency (hemophilia C) causes only mild bleeding, mostly after surgery. Inhibiting FXI may provide anticoagulation with lower bleeding risk.

Agents in Development:

Asundexian (BAY 2433334): Oral FXIa inhibitor, Phase 3 trials ongoing
Abelacimab: Monoclonal antibody against FXI, subcutaneous monthly dosing
Milvexian: Oral FXIa inhibitor

Potential Applications:

VTE prevention post-orthopedic surgery
Stroke prevention in atrial fibrillation
APS (theoretical—less thrombin generation, preserved hemostasis)

Status: Awaiting Phase 3 trial results. May revolutionize anticoagulation by uncoupling antithrombotic efficacy from bleeding risk.

Extended Half-Life Factor Concentrates for Deficiencies

Problem: Protein C, Protein S, Antithrombin concentrates have short half-lives (hours to 1-2 days), requiring frequent infusions.

Solution: PEGylation and Fc fusion technology to extend half-life.

Current Options:

Antithrombin concentrates: Available for acute thrombosis in AT deficiency or high-risk procedures (e.g., surgery, childbirth)
Protein C concentrates: Available for purpura fulminans, acute thrombosis in severe deficiency

Future: Gene therapy for inherited thrombophilias (early preclinical stages).

Biomarkers for Thrombotic Risk Stratification

Emerging markers:

Thrombin generation assays: Measure endogenous thrombin potential (ETP)—elevated in thrombophilia, may predict recurrent VTE better than single factor deficiencies
D-dimer at anticoagulation cessation: Elevated D-dimer 1 month after stopping anticoagulation predicts recurrent VTE (PROLONG study)
Microparticle analysis: Procoagulant microparticles from platelets/endothelium correlate with thrombotic risk in cancer, APS

Clinical Application: Not yet standard of care, but may allow personalized anticoagulation duration decisions in the future.

Case-Based Learning: Bringing It Together

Case 1: The Young Woman with Recurrent DVT

Presentation: 32-year-old woman presents with left leg swelling. Ultrasound confirms left femoral-popliteal DVT. History reveals:

Right leg DVT 4 years ago after starting oral contraceptives (treated for 6 months, stopped OCPs)
Two spontaneous miscarriages at 8 and 10 weeks gestation
Mother had DVT at age 45

What do you test?

Priority: Antiphospholipid Syndrome

Lupus anticoagulant
Anticardiolipin IgG/IgM
Anti-β2-glycoprotein-I IgG/IgM

Rationale: Recurrent VTE + recurrent pregnancy loss = classic APS presentation. Young age + arterial AND venous thrombosis potential makes APS highest priority.

Result: Positive lupus anticoagulant, high-titer anticardiolipin IgG (65 GPL), positive anti-β2GPI IgG.

Confirmation: Repeat in 12 weeks → persistently positive (all three antibodies).

Diagnosis: Triple-positive Antiphospholipid Syndrome.

Management:

Indefinite anticoagulation with warfarin INR 2-3 (NOT DOACs—triple-positive, high-risk)
Counsel about future pregnancy: LMWH therapeutic dose + aspirin 81 mg throughout pregnancy and postpartum
Screen for SLE: ANA, dsDNA, complement (C3, C4)
Avoid estrogen-containing contraceptives lifelong

Pearl: This case illustrates why clinical phenotyping matters. The combination of VTE + obstetric complications pointed directly to APS, making testing high-yield.

Case 2: The Man with Splanchnic Thrombosis

Presentation: 48-year-old man with 2 weeks of progressive abdominal pain, early satiety, and nausea. CT abdomen shows portal vein thrombosis with splenomegaly (14 cm). Labs:

Hemoglobin 17.2 g/dL
Platelets 520,000/μL
WBC 14,500/μL
LDH 380 U/L (mildly elevated)

What do you test?

Priority:

JAK2 V617F mutation (high pretest probability for MPN)
PNH flow cytometry (abdominal vein thrombosis)
Antiphospholipid antibodies (less likely given thrombocytosis, but comprehensive)

Result: JAK2 V617F positive (allele burden 38%).

Additional Testing:

Bone marrow biopsy: Hypercellular with megakaryocytic and granulocytic proliferation, increased reticulin fibrosis (Grade 1)
Erythropoietin level: Normal (rules out Polycythemia Vera as primary diagnosis)

Diagnosis: Essential Thrombocythemia with JAK2 V617F mutation, complicated by portal vein thrombosis.

Management:

Anticoagulation: Start therapeutic LMWH (enoxaparin 1 mg/kg q12h), transition to warfarin (INR 2-3) or DOAC (apixaban 5 mg BID) for indefinite duration
Aspirin 81 mg daily (proven to reduce thrombotic events in ET)
Cytoreduction with hydroxyurea: Start 500-1,000 mg daily, titrate to platelet count <400,000 (high-risk ET based on age >60 criteria approaching and thrombosis history)
Hematology follow-up for long-term MPN management
Monitor for portal hypertension complications (varices—refer for EGD)

Oyster: Splanchnic vein thrombosis should ALWAYS prompt JAK2 testing. In this case, the elevated hemoglobin and platelets were clinical clues, but even with normal CBC, JAK2 should be checked.

Case 3: The Woman with Dark Urine and Abdominal Pain

Presentation: 38-year-old woman presents with severe abdominal pain and dark urine for 3 days. CT abdomen/pelvis shows hepatic vein thrombosis (Budd-Chiari syndrome). Labs:

Hemoglobin 9.8 g/dL (baseline 13)
Platelets 95,000/μL
WBC 3,200/μL
LDH 1,450 U/L (markedly elevated)
Haptoglobin <10 mg/dL (undetectable)
Indirect bilirubin 3.2 mg/dL
Reticulocyte count 8% (elevated)
Direct Coombs test: Negative

What do you test?

Priority: PNH Flow Cytometry

Rationale: Triad of intravascular hemolysis (high LDH, low haptoglobin, reticulocytosis, negative Coombs) + thrombosis in unusual site (hepatic vein) + cytopenias = PNH until proven otherwise.

Result: Flow cytometry shows 68% GPI-anchor deficient granulocytes, 55% GPI-anchor deficient RBCs (large PNH clone).

Diagnosis: Paroxysmal Nocturnal Hemoglobinuria complicated by Budd-Chiari syndrome.

Management:

Immediate: Therapeutic anticoagulation (LMWH or heparin), avoid warfarin initially (acute illness, potential hepatic dysfunction from Budd-Chiari)
Urgent complement inhibition: Start eculizumab (after meningococcal vaccination + antibiotic prophylaxis)
- Discuss with hematology STAT
- Eculizumab dramatically reduces hemolysis and thrombotic risk
Indefinite anticoagulation: Transition to warfarin (INR 2-3) or DOAC once stable, continue lifelong
Supportive care: Folic acid, iron supplementation (chronic hemoglobinuria → iron loss), transfusion support as needed
Monitor for portal hypertension, consider TIPS if hepatic vein thrombosis causing refractory ascites
Bone marrow biopsy to assess for aplastic anemia component

Pearl: PNH is rare but catastrophic if missed. The markedly elevated LDH (>1,000) in the setting of hemolytic anemia with negative Coombs is the key clue. Don't delay flow cytometry.

Case 4: The Man with Migratory Thrombophlebitis

Presentation: 62-year-old man with 6 months of recurrent painful, erythematous nodules on arms and legs that migrate every 2-3 weeks. No prior VTE. Two weeks ago, developed left calf DVT despite aspirin. Now presents with new right arm superficial thrombophlebitis. 10-pound weight loss over 3 months, mild epigastric discomfort.

What do you think and test?

Clinical Impression: Trousseau's Syndrome—migratory superficial thrombophlebitis + weight loss + GI symptoms = high suspicion for visceral malignancy, especially pancreatic cancer.

Testing:

Immediate: CT chest/abdomen/pelvis with IV contrast (cancer staging)
Labs: CBC, CMP, LFTs (assess for biliary obstruction), CA 19-9 (tumor marker for pancreatic cancer)
Thrombophilia panel: Antiphospholipid antibodies, JAK2 (completeness, but cancer is leading diagnosis)

Result:

CT: 3.5 cm mass in pancreatic head with biliary duct dilation, multiple liver metastases
CA 19-9: 1,850 U/mL (markedly elevated, normal <37)
Biopsy (EUS-guided): Adenocarcinoma

Diagnosis: Metastatic pancreatic adenocarcinoma with Trousseau's syndrome.

Management:

Anticoagulation: LMWH (dalteparin 200 units/kg SC daily x 1 month, then 150 units/kg daily) indefinitely
- Avoid DOACs in setting of potential GI bleeding risk from tumor
Oncology referral: Palliative chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel)
Supportive care: Pain management, biliary stenting if obstruction worsens
Monitor for recurrent thrombosis (common despite anticoagulation in advanced pancreatic cancer)

Oyster: Migratory superficial thrombophlebitis in non-varicose veins is NOT benign. This presentation has 50% association with visceral malignancy. Aggressive cancer screening is warranted.

Pearl: Pancreatic cancer has the HIGHEST VTE risk of all malignancies (20-30% incidence). Even without Trousseau's, unprovoked VTE in older patient warrants pancreatic protocol CT.

Conclusion

The patient with recurrent DVTs presents a diagnostic challenge that requires clinical acumen, judicious use of testing, and individualized management. The key principles are:

Test strategically, not reflexively: Avoid "shotgun" thrombophilia panels. Use clinical phenotyping to guide targeted testing.
Acquired thrombophilias are often more important than inherited: In adults, focus on APS, myeloproliferative neoplasms, PNH, and malignancy before ordering genetic tests.
Timing of testing matters: Protein C, S, and Antithrombin are affected by anticoagulation and acute illness. Genetic tests (Factor V Leiden, Prothrombin) can be done anytime.
Confirm abnormalities before making lifelong treatment decisions: Single positive test ≠ diagnosis. Repeat testing is mandatory, especially for antiphospholipid antibodies (12 weeks) and protein deficiencies.
Individualize anticoagulation decisions: Consider bleeding risk, patient preference, thrombosis burden, and specific thrombophilia when deciding on duration and choice of anticoagulant.
Know when specific therapies are required: Triple-positive APS requires warfarin, not DOACs. PNH with thrombosis requires complement inhibition. MPN-associated thrombosis requires cytoreduction plus anticoagulation.
Communicate clearly with patients: Explain that not finding a cause doesn't mean there isn't one, and that having a thrombophilia doesn't always change management but provides important information for family planning and risk counseling.

The landscape of thrombophilia diagnosis and management continues to evolve. Direct oral anticoagulants have simplified long-term anticoagulation for many patients, but certain thrombophilias (APS, cancer) require traditional agents. Novel therapies (Factor XI inhibitors, extended half-life concentrates, complement inhibitors) promise to improve outcomes while reducing bleeding risk.

Ultimately, excellence in managing recurrent thrombosis requires synthesizing clinical presentation, laboratory data, and patient values to deliver personalized, evidence-based care.

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Appendix A: Quick Reference Tables

Table 1: Thrombophilia Testing Summary

Test	What It Detects	Can Test On Anticoagulation?	Timing Considerations	Clinical Significance
Factor V Leiden (genetic)	G1691A mutation	YES (anytime)	None	Weak thrombophilia (heterozygous); strong (homozygous)
Prothrombin G20210A (genetic)	G20210A mutation	YES (anytime)	None	Weak thrombophilia
Protein C (functional)	Protein C activity	NO (warfarin depletes)	Off warfarin x4 weeks; avoid acute thrombosis	Moderate-strong thrombophilia
Protein S (functional)	Free Protein S activity	NO (warfarin depletes)	Off warfarin x4 weeks; affected by pregnancy, OCPs, inflammation	Moderate-strong thrombophilia
Antithrombin (functional)	Antithrombin activity	NO (heparin consumes)	Off heparin; avoid acute thrombosis	STRONGEST inherited thrombophilia
Lupus anticoagulant	Phospholipid-dependent inhibitor	NO (heparin interferes)	Can test on warfarin (less reliable); best before anticoagulation	STRONGEST acquired thrombophilia
Anticardiolipin IgG/IgM	Antibodies to cardiolipin-β2GPI	YES (anytime)	Repeat in 12 weeks for confirmation	Part of APS criteria
Anti-β2GPI IgG/IgM	Antibodies to β2-glycoprotein-I	YES (anytime)	Repeat in 12 weeks for confirmation	Most specific for APS
JAK2 V617F	JAK2 mutation	YES (anytime)	None	Diagnostic for MPN (PV 95%, ET/PMF 50%)
PNH flow cytometry	GPI-anchor deficiency	YES (anytime)	Best on WBCs (granulocytes/monocytes)	Diagnostic for PNH

Table 2: Anticoagulation Recommendations by Thrombophilia

Thrombophilia	After 1st Unprovoked VTE	After 2nd VTE	Special Considerations
None identified	3-6 months; reassess bleeding risk	Indefinite	Consider extended if male, elevated D-dimer at cessation
Heterozygous FVL	3-6 months	Indefinite	Weak thrombophilia; doesn't mandate indefinite after 1st event
Heterozygous Prothrombin G20210A	3-6 months	Indefinite	Weak thrombophilia; doesn't mandate indefinite after 1st event
Homozygous FVL or compound heterozygote	Indefinite	Indefinite	High-risk thrombophilia
Protein C deficiency (severe <20%)	Indefinite	Indefinite	Bridge with heparin when starting warfarin
Protein S deficiency (severe <30%)	Indefinite	Indefinite	Bridge with heparin when starting warfarin
Antithrombin deficiency	INDEFINITE (always)	Indefinite	May need higher LMWH doses; DOACs preferred
Antiphospholipid syndrome	INDEFINITE	Indefinite	Warfarin preferred (INR 2-3); avoid DOACs if high-risk
Myeloproliferative neoplasm	Indefinite	Indefinite	Add aspirin + cytoreduction (hydroxyurea)
PNH	Indefinite	Indefinite	Add eculizumab/ravulizumab (complement inhibition)
Active cancer	Indefinite (until cured)	Indefinite	LMWH preferred; apixaban acceptable alternative (avoid GI/GU cancers)

Table 3: Anticoagulant Selection Guide

Clinical Scenario	First-Line	Alternatives	Avoid
Standard VTE (no thrombophilia)	DOAC (apixaban, rivaroxaban, edoxaban)	Warfarin, LMWH	N/A
APS (triple-positive or arterial event)	Warfarin INR 2-3	NONE	DOACs
APS (low-risk, single/double positive)	Warfarin INR 2-3	DOACs (controversial, shared decision)	N/A
Cancer-associated VTE	LMWH (dalteparin, enoxaparin)	Apixaban, rivaroxaban	DOACs in GI/GU malignancies
Antithrombin deficiency	DOAC (apixaban, rivaroxaban)	LMWH (may need higher dose), warfarin	N/A
Protein C/S deficiency	DOAC OR warfarin (bridge with heparin)	LMWH	Warfarin without heparin bridge
Pregnancy	LMWH (enoxaparin, dalteparin)	NONE in pregnancy	Warfarin (teratogenic), DOACs (insufficient data)
Severe renal impairment (CrCl <30)	Warfarin	Apixaban 2.5 mg BID (if CrCl 15-29)	Rivaroxaban, edoxaban, dabigatran, LMWH
Recurrent VTE on warfarin	Increase INR to 2.5-3.5 OR switch to LMWH	DOAC (if wasn't on one)	Continuing same regimen
Recurrent VTE on DOAC	Switch to LMWH	Switch to different DOAC OR warfarin	Continuing same DOAC

Table 4: When to Consult Hematology

Scenario	Urgency	Rationale
Suspected or confirmed APS with arterial thrombosis	Urgent	Complex management; may need dual therapy (warfarin + antiplatelet)
Catastrophic APS (multi-organ thrombosis)	EMERGENT	Life-threatening; needs IVIG, plasma exchange, immunosuppression
Suspected or confirmed PNH	Urgent	Needs complement inhibitor (eculizumab/ravulizumab); meningococcal vaccination required
Myeloproliferative neoplasm with thrombosis	Non-urgent	Needs cytoreduction, long-term MPN monitoring
Antithrombin deficiency	Urgent	May need antithrombin concentrate for acute events; complex dosing
Recurrent VTE despite therapeutic anticoagulation	Urgent	May need escalation, IVC filter consideration, workup for occult malignancy
Warfarin-induced skin necrosis	EMERGENT	Stop warfarin immediately; may need Protein C concentrate, debridement
Splanchnic vein thrombosis with unclear etiology	Non-urgent	Comprehensive workup (JAK2, PNH, APS, liver disease)
Pregnancy with thrombophilia and prior VTE	Non-urgent (preconception)	LMWH dosing, monitoring, delivery planning
Pediatric thrombosis	Urgent	Age-specific considerations, different reference ranges, family counseling

Appendix B: Anticoagulation Dosing Reference

Low Molecular Weight Heparin (LMWH)

Enoxaparin:

Prophylactic: 40 mg SC daily (30 mg SC daily if CrCl 15-30)
Intermediate: 40 mg SC q12h
Therapeutic: 1 mg/kg SC q12h OR 1.5 mg/kg SC daily
Renal dosing: If CrCl <30, use 1 mg/kg SC daily (avoid if CrCl <15)

Dalteparin:

Prophylactic: 5,000 units SC daily
Cancer VTE: 200 units/kg SC daily x 1 month, then 150 units/kg SC daily
Therapeutic: 200 units/kg SC daily (or 100 units/kg SC q12h)

Tinzaparin:

Prophylactic: 4,500 units SC daily (3,500 units if <50 kg; 75 units/kg if >70 kg)
Therapeutic: 175 units/kg SC daily

Monitoring:

Generally not required for prophylactic or standard therapeutic dosing
Consider anti-Xa monitoring in: extremes of weight (<50 kg, >150 kg), renal impairment (CrCl 30-50), pregnancy (third trimester), recurrent VTE on LMWH
Target anti-Xa levels:
- BID dosing: 0.6-1.0 units/mL (peak, 4 hours post-dose)
- Daily dosing: 1.0-2.0 units/mL (peak, 4 hours post-dose)

Direct Oral Anticoagulants (DOACs)

Apixaban (Eliquis):

VTE treatment: 10 mg PO BID x 7 days, then 5 mg PO BID
VTE prophylaxis (post-orthopedic surgery): 2.5 mg PO BID
Atrial fibrillation: 5 mg PO BID (2.5 mg BID if ≥2 of: age ≥80, weight ≤60 kg, SCr ≥1.5)
Renal dosing: If CrCl 15-29, use 2.5 mg BID for VTE; avoid if CrCl <15

Rivaroxaban (Xarelto):

VTE treatment: 15 mg PO BID x 21 days, then 20 mg PO daily
VTE extended prophylaxis: 10 mg PO daily (after 6 months of treatment)
Take with food (increases absorption by 50%)
Renal dosing: If CrCl 30-50, use 15 mg daily (after initial BID phase); avoid if CrCl <30

Edoxaban (Savaysa):

VTE treatment: Treat with LMWH/heparin x 5-10 days first, then 60 mg PO daily
Renal dosing: 30 mg daily if CrCl 15-50, weight ≤60 kg, or on P-gp inhibitors; avoid if CrCl <15 or >95
Do NOT use as initial monotherapy (must use parenteral anticoagulant first)

Dabigatran (Pradaxa):

VTE treatment: Treat with LMWH/heparin x 5-10 days first, then 150 mg PO BID
Renal dosing: Avoid if CrCl <30
Consider 110 mg BID if: age ≥75-80, CrCl 30-50, high bleeding risk, on interacting medications
Take with food (reduces dyspepsia)

Warfarin

Initiation:

Typical starting dose: 5 mg daily (2.5 mg if elderly, frail, or high bleeding risk)
Overlap with heparin/LMWH for minimum 5 days AND until INR therapeutic x 2 consecutive days
Check INR daily initially, then q2-3 days until stable, then weekly, then monthly

Target INR:

Standard VTE: 2-3 (target 2.5)
APS: 2-3 (NOT higher; no benefit of 3-4 shown in trials)
Mechanical heart valves: Depends on valve type/position (2.5-3.5 for mitral, some aortic)
Recurrent VTE on warfarin: Consider 2.5-3.5 (upper end of range)

Reversal:

Non-urgent (INR 4.5-10, no bleeding): Hold 1-2 doses, resume at lower dose
Urgent (INR >10 or minor bleeding): Vitamin K 2.5-5 mg PO
Major bleeding: 4-factor PCC (prothrombin complex concentrate) 25-50 units/kg IV + Vitamin K 10 mg IV (slow infusion)

Reversal Agents

Anticoagulant	Reversal Agent	Dose	Notes
Warfarin	Vitamin K (phytonadione)	2.5-10 mg PO/IV	IV: slow infusion (anaphylaxis risk); effect in 6-24 hours
	4-Factor PCC (Kcentra)	25-50 units/kg IV	Immediate reversal; expensive
	Fresh Frozen Plasma (FFP)	10-15 mL/kg IV	Less effective than PCC; volume overload risk
Heparin (UFH)	Protamine sulfate	1 mg per 100 units heparin (max 50 mg)	Give within 2 hours of heparin; anaphylaxis risk
LMWH	Protamine sulfate	1 mg per 1 mg enoxaparin (50% neutralization)	Less effective than for UFH
Dabigatran	Idarucizumab (Praxbind)	5 g IV (two 2.5 g doses)	Immediate reversal; expensive; specific antidote
Xa inhibitors (apixaban, rivaroxaban, edoxaban)	Andexanet alfa (Andexxa)	Low dose: 400 mg bolus + 4 mg/min x 2h <br> High dose: 800 mg bolus + 8 mg/min x 2h	Immediate reversal; extremely expensive; specific antidote
	4-Factor PCC	25-50 units/kg IV	Alternative if andexanet unavailable

Appendix C: Patient Education Resources

Key Counseling Points for Patients with Thrombophilia

General Education:

What is thrombophilia? "Your blood has a higher tendency to clot than normal. This is due to [specific cause], which [explain mechanism in lay terms]."
Why did I get a clot? "Blood clots usually happen when multiple risk factors come together. Your thrombophilia is one factor, but [surgery/immobility/pregnancy/etc.] was likely the trigger."
Will I need medication forever? "It depends on several factors: the type of thrombophilia, whether you've had one or multiple clots, and your risk of bleeding. We'll make this decision together based on your individual situation."

Lifestyle Modifications:

Stay active: Regular exercise improves circulation and reduces clot risk
Hydration: Especially during illness, travel, hot weather
Avoid prolonged immobility: Get up and move every 1-2 hours during long flights, car rides, or desk work
Leg exercises: Ankle pumps, calf raises when seated for long periods
Compression stockings: For travel >4 hours (knee-high, 15-30 mmHg)

Medication Adherence:

Take as prescribed: Missing doses increases clot risk
Warfarin: Consistent Vitamin K intake (leafy greens okay, just be consistent); avoid cranberry juice, excessive alcohol
DOACs: Take with food if rivaroxaban or dabigatran; apixaban and edoxaban can be taken without food
LMWH injections: Rotate sites (abdomen, thighs); proper technique; safe disposal of needles

When to Seek Medical Attention:

Signs of DVT: Unilateral leg swelling, pain, warmth, redness
Signs of PE: Sudden shortness of breath, chest pain (worse with deep breath), coughing blood, rapid heart rate
Signs of bleeding (on anticoagulation): Severe headache, vision changes, bleeding that won't stop, black/tarry stools, blood in urine, easy bruising

Women's Health:

Contraception: Avoid estrogen-containing birth control pills, patches, rings. Safe options: progestin-only pill, IUD, implant, barrier methods
Pregnancy planning: Discuss with hematology and maternal-fetal medicine BEFORE conception. May need LMWH throughout pregnancy
HRT in menopause: Generally avoid estrogen; non-hormonal options preferred

Family Considerations:

Should my family be tested? Depends on type of thrombophilia and family history. Generally consider testing if:
- Severe inherited deficiency (Protein C/S/AT, homozygous FVL)
- Multiple family members affected
- Family members facing high-risk situations (pregnancy, surgery, long travel)
Not all family members need testing: Heterozygous FVL or Prothrombin G20210A alone typically don't warrant cascade family screening

Travel Precautions:

Flights >4 hours:
- Aisle seat (easier to move around)
- Walk every 1-2 hours
- Hydrate well (avoid excess alcohol/caffeine)
- Ankle/calf exercises while seated
- Compression stockings
- Consider prophylactic LMWH injection before very long flights (>8 hours) if high-risk thrombophilia and not on anticoagulation
Travel with medications:
- Carry anticoagulant in carry-on (not checked luggage)
- Bring extra supply in case of delays
- Travel letter from physician (especially for LMWH syringes through security)

Medical Alert:

Wear medical alert bracelet/necklace: Especially if on anticoagulation or have severe thrombophilia
Inform all healthcare providers: Dentists, surgeons, emergency physicians about thrombophilia and anticoagulation status

Appendix D: Anticoagulation in Special Situations

Perioperative Management

Low Bleeding Risk Procedures (can continue anticoagulation):

Dental cleaning, simple extractions
Cataract surgery
Endoscopy without biopsy
Superficial skin procedures

High Bleeding Risk Procedures (need to stop anticoagulation):

Anticoagulant	Stop Before Surgery	Resume After Surgery	Bridge if High VTE Risk?
Warfarin	5 days (check INR <1.5 day before)	Evening of surgery or POD1	YES (LMWH) if: mechanical valve, recent VTE (<3 months), high-risk thrombophilia
Apixaban	2-3 days (CrCl >50: 2 days; <50: 3 days)	24-48 hours post-op	Generally NO (short half-life)
Rivaroxaban	2-3 days (CrCl >50: 2 days; <50: 3 days)	24-48 hours post-op	Generally NO
Edoxaban	2-3 days (CrCl >50: 2 days; <50: 3 days)	24-48 hours post-op	Generally NO
Dabigatran	3-5 days (depends on CrCl)	24-48 hours post-op	Generally NO
LMWH	24 hours (prophylactic); 24 hours (therapeutic)	12-24 hours post-op	Already on short-acting agent

Bridging Strategy (if needed):

Stop warfarin 5 days before surgery
Start therapeutic LMWH when INR <2 (usually day 3)
Last LMWH dose 24 hours before surgery
Resume LMWH 12-24 hours post-op (if hemostasis adequate)
Restart warfarin evening of surgery or POD1
Stop LMWH when INR therapeutic x 2 days

Pearl: Most patients do NOT need bridging. Bridging increases bleeding risk ~3-fold. Reserve for: mechanical valves, VTE within 3 months, APS with arterial thrombosis, atrial fibrillation with CHADS2 ≥5.

Anticoagulation and Procedures

Neuraxial Anesthesia (Epidural/Spinal):

High risk of spinal hematoma with anticoagulation
Timing requirements:
- Prophylactic LMWH: Hold ≥12 hours
- Therapeutic LMWH: Hold ≥24 hours
- Warfarin: INR <1.5
- Apixaban/rivaroxaban: Hold ≥48-72 hours
- Dabigatran: Hold ≥72-96 hours
Catheter removal: Wait ≥4 hours after last prophylactic LMWH dose

Cardioversion:

Therapeutic anticoagulation x3 weeks before cardioversion
Continue indefinitely after (atrial fibrillation recurrence risk)
TEE-guided approach: Can cardiovert sooner if no LA thrombus + therapeutic anticoagulation initiated

Anticoagulation and Bleeding

Minor Bleeding (manageable):

Continue anticoagulation if possible
Local measures (pressure, ice, topical agents)
Review concurrent medications (antiplatelets, NSAIDs—consider stopping)

Major Bleeding (requires reversal):

Life-threatening sites: Intracranial, intraocular, pericardial, retroperitoneal, massive GI
Hemodynamic instability: Hypotension, tachycardia despite resuscitation
Transfusion requirement: >2 units pRBCs or rapid ongoing bleeding

Management:

Stop anticoagulant
Administer reversal agent (see Appendix B)
Transfuse as needed (pRBCs, platelets if thrombocytopenic or on antiplatelet agents)
Surgical/endoscopic hemostasis if indicated
Restart anticoagulation when safe (typically 7-14 days, individualized)

Final Thoughts: The Art and Science of Thrombophilia Management

Managing patients with recurrent thrombosis requires balancing evidence-based medicine with individualized care. Key principles include:

Clinical context always trumps laboratory values: A weakly positive aCL antibody in isolation doesn't equal APS. A Factor V Leiden mutation doesn't automatically mandate lifelong anticoagulation.
Test strategically, not reflexively: Avoid shotgun panels. Use clinical phenotyping to guide targeted testing that will actually change management.
Timing matters: Many tests are affected by anticoagulation, acute illness, and physiologic states. Know when to test and when to defer.
Confirm before committing: Single abnormal results require confirmation before making lifelong treatment decisions.
Acquired thrombophilias often matter more: In adults, focus on APS, MPNs, PNH, and malignancy—these require specific therapies beyond standard anticoagulation.
Shared decision-making is essential: Anticoagulation duration involves trade-offs between thrombotic and bleeding risk. Engage patients in these decisions with clear communication about risks and benefits.
Stay current: The field evolves rapidly. DOACs have transformed VTE treatment, but certain conditions (APS, cancer) still require traditional agents. Factor XI inhibitors may be the next revolution.

The goal is not to test every patient with every test, but to identify the subset of patients whose thrombophilia will change management—whether that's anticoagulation duration, choice of agent, family counseling, or treatment of underlying disease.

Excellence in this field comes from synthesizing clinical acuity, laboratory interpretation, and patient preferences to deliver personalized, evidence-based care that improves outcomes and quality of life.

*This document is intended for educational purposes for postgraduate medical trainees and practicing physicians. All clinical decisions should be individualized based on patient-specific factors, institutional protocols, and current evidence-based guidelines. Consult hematology for complex cases.*d prolonged aPTT

The Three Tests:

1. Lupus Anticoagulant (LA):

Mechanism: Antibodies against phospholipid-binding proteins prolong phospholipid-dependent coagulation tests in vitro (paradoxically, procoagulant in vivo).

Testing protocol:

Screening test (dilute Russell viper venom time, dRVVT; or aPTT)
If prolonged, mixing study (1:1 patient plasma + normal plasma)
If doesn't correct → inhibitor present
Confirmatory test with excess phospholipid (should correct if LA; won't correct if factor inhibitor)

Interpretation:

Positive LA: Most specific for thrombosis (75% thrombotic risk if positive)
Strongest predictor of recurrent thrombosis

Timing issues:

Cannot test on heparin/LMWH (interferes with all coagulation assays)
Can test on DOACs with some specialized assays, but ideally test before starting anticoagulation
Can test on warfarin but results less reliable (warfarin prolongs aPTT baseline)

Pearl: If patient already anticoagulated and you need to test, DOACs have shortest half-life. Hold apixaban/rivaroxaban x48 hours, check trough levels (should be undetectable), then test.

2. Anticardiolipin Antibodies (aCL):

Mechanism: Antibodies against cardiolipin-β2-glycoprotein-I complexes.

Testing:

ELISA for IgG and IgM
Report in GPL units (IgG phospholipid units) or MPL units (IgM)
Medium-to-high titer: >40 GPL/MPL or >99th percentile

Interpretation:

Low-titer positives (<40): Clinically insignificant, often transient
IgG more clinically significant than IgM
High titer (>80): Strong association with thrombosis

Timing:

Can test anytime (not affected by anticoagulation)

3. Anti-β2-Glycoprotein-I Antibodies (anti-β2GPI):

Mechanism: Direct antibodies against β2-glycoprotein-I (the key antigenic protein in APS).

Testing:

ELISA for IgG and IgM
Report as units or multiples of cutoff

Interpretation:

Most specific for APS (when medium-to-high titer)
IgG more clinically significant

Timing:

Can test anytime

Diagnostic Algorithm

Clinical suspicion for APS
↓
Order all three tests:
- Lupus anticoagulant
- Anticardiolipin IgG/IgM
- Anti-β2GPI IgG/IgM
↓
ANY test positive?
↓ YES
Repeat ALL tests in ≥12 weeks
(Must confirm persistence)
↓
≥1 test persistently positive?
↓ YES
Diagnose APS (if clinical criteria met)

Oyster: Don't diagnose APS based on weakly positive aCL or anti-β2GPI (low titer) without positive lupus anticoagulant. LA is the gold standard.

Hack: If patient has thrombosis + positive antibodies but you haven't confirmed with repeat testing yet, start anticoagulation as you would for any VTE. The 12-week confirmation period is for DIAGNOSIS, not for withholding treatment.

Management: Warfarin vs. DOACs—The Controversy

Standard APS with Venous Thrombosis:

First-line: Warfarin

Target INR 2-3 (NOT higher; WAPS trial showed no benefit of INR 3-4)
Indefinite duration (very high recurrence risk off anticoagulation)

DOACs in APS: The Evidence Crisis

Three RCTs compared DOACs to warfarin in APS:

TRAPS Trial (2016): Rivaroxaban vs warfarin in triple-positive APS → terminated early due to excess arterial thrombosis in rivaroxaban arm (4 strokes vs 0)
RAPS Trial (2019): Rivaroxaban vs warfarin in low-risk APS (single or double positive, venous thrombosis only) → non-inferiority NOT established, trend toward more events with rivaroxaban
ASTRO-APS Trial (2022): Apixaban vs warfarin in APS → non-inferior for primary outcome, but underpowered, short follow-up

Current Consensus:

APS Risk Profile	Thrombosis Type	Recommended Anticoagulant
High-risk (triple-positive, previous arterial thrombosis, CAPS)	Any	Warfarin INR 2-3 (DOACs contraindicated)
Standard-risk (double-positive or single-positive LA)	Venous	Warfarin INR 2-3 preferred; DOACs controversial
Low-risk (single-positive aCL or anti-β2GPI, NOT LA)	Venous	Warfarin OR DOACs (shared decision-making)
Any risk profile	Arterial thrombosis	Warfarin INR 2-3 + antiplatelet (DOACs NOT recommended)

Oyster: The thrombotic events on DOACs in APS trials were predominantly ARTERIAL (strokes). If your APS patient has had arterial thrombosis or is triple-positive, DOACs are contraindicated. Use warfarin.

Management Pearls:

"Seronegative APS": Some patients meet clinical criteria for APS (e.g., recurrent miscarriages + thrombosis) but test negative. This is controversial. Most experts treat as APS if clinical phenotype compelling.
Antiplatelet + anticoagulation: Consider low-dose aspirin 81 mg PLUS warfarin in:
- Arterial thrombosis
- Recurrent thrombosis despite therapeutic anticoagulation
- Triple-positive APS
Pregnancy management:
- History of VTE: LMWH therapeutic dose throughout pregnancy
- Obstetric APS (pregnancy loss only, no VTE): LMWH prophylactic dose + low-dose aspirin
- Both reduce pregnancy loss from 90% to 30%
Monitor for thrombocytopenia: 20-30% of APS patients have mild thrombocytopenia (50,000-150,000). Usually does NOT require treatment, NOT a contraindication to anticoagulation.
Screen for SLE: Check ANA, dsDNA, complement (C3, C4). 20-30% of APS patients have or will develop SLE.

Myeloproliferative Neoplasms (MPN): The JAK2 Mutation and Aspirin

Myeloproliferative neoplasms—particularly Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF)—are MAJOR causes of:

Splanchnic vein thrombosis (25-50% of Budd-Chiari, portal vein thrombosis)
Recurrent VTE despite anticoagulation
Arterial thrombosis in young patients

Clinical Clues for MPN-Associated Thrombosis

When to suspect:

Splanchnic vein thrombosis (hepatic, portal, mesenteric, splenic veins)—MPN present in 30-40%
Cerebral venous sinus thrombosis
Recurrent VTE, especially with elevated platelet count or hematocrit
VTE in young patient with isolated thrombocytosis (platelets >450,000)
Erythromelalgia (burning pain, redness of hands/feet, relieved by aspirin)
Aquagenic pruritus (itching after hot shower)

Monday, October 6, 2025