How should protein C deficiency be evaluated and managed, including acute venous thromboembolism treatment, long‑term anticoagulation decisions, pregnancy considerations, and severe neonatal presentations?

Protein C Deficiency: Evaluation and Management

Acute Presentation and Diagnosis

For severe homozygous protein C deficiency presenting as neonatal purpura fulminans, protein C replacement therapy is the primary intervention, offering superior long-term effectiveness compared to anticoagulation alone. 1, 2

Diagnostic Testing Considerations

• Chromogenic assay is the recommended laboratory test for diagnosing protein C deficiency due to good specificity, though it fails to detect rare type 2b deficiency where the defect involves poor calcium ion and phospholipid interaction 3
• Clotting-based assays can detect type 2b deficiency but have reduced specificity and are falsely elevated by direct oral anticoagulants 3
• Age-specific reference ranges must be used—adult ranges cannot be applied to infants or children, as levels may not reach adult values even in adolescence 3
• Testing should be targeted only when results will influence treatment decisions, particularly in patients with recurrent VTE or strong family history 2

Clinical Presentations by Severity

Homozygous/Severe Deficiency (protein C activity <1 IU/dL):

• Presents in neonatal period with purpura fulminans and severe disseminated intravascular coagulation, often with concomitant venous thromboembolism 4
• Historical mortality rate of 5% and pulmonary embolism rate of 38% when treated with anticoagulation alone 2
• Recurrent thrombotic episodes (purpura fulminans, DIC, or VTE) are common 4

Heterozygous/Mild Deficiency:

• Often asymptomatic but increases VTE risk 5-10 fold in thrombosis-prone families 3
• May present with superficial thrombophlebitis, deep venous thrombosis, pulmonary embolism, cerebral venous thrombosis, or mesenteric vein thrombosis 5
• Protein C deficiency is an independent risk factor with odds ratio of 11.1 for cerebral venous thrombosis 2
• Heterozygous deficiency alone does not determine thrombophilia—patients lacking additional risk factors like factor V Leiden may never experience VTE 3

Acute Management of Homozygous Protein C Deficiency

First-Line Treatment

Protein C replacement is superior to anticoagulation alone for acute purpura fulminans episodes 1, 2:

• Administer protein C concentrate or fresh-frozen plasma for acute exacerbations 2
• Replacement therapy provides long-term effectiveness without the bleeding risks of high-intensity anticoagulation 2
• Typical acute management requires replacement with protein C concentrate while maintaining therapeutic anticoagulation 4

Alternative When Cost is Prohibitive

When full protein C replacement cannot be implemented due to cost constraints, use combination therapy with anticoagulation plus protein C replacement rather than anticoagulation alone 1, 2:

• This approach reduces the required intensity of anticoagulation and consequently reduces bleeding risk 1, 2
• Protein C is expensive, with financial burden increasing as children grow due to weight-based dosing 2

Critical Warfarin Initiation Warning

If warfarin must be used, there is serious risk of paradoxical worsening with coumarin-induced skin necrosis during initiation 2, 6:

• Start warfarin at low doses under coverage of therapeutic parenteral anticoagulation (heparin or LMWH) 2
• Overlap with heparin anticoagulation to prevent coumarin-induced hemorrhagic skin necrosis 5
• Gradually increase warfarin dose over 1 or more weeks 2
• Heparin alone appears ineffective in preventing purpura fulminans syndrome 5

Long-Term Management Strategies

For Homozygous Protein C Deficiency

Three main options exist, with choice depending on family values, local resources, and cost considerations 1, 2:

1. Continued protein C replacement therapy (preferred but increasingly expensive as child grows) 2
2. Combined protein C replacement with reduced-intensity anticoagulation (when full replacement is cost-prohibitive) 1, 2
3. Liver transplantation (curative but carries significant acute and chronic risks) 1, 2

Liver transplantation should be discussed early, before progressive organ damage occurs 1, 2:

• Curative of protein C deficiency but has its own acute and chronic risks and burden of care 1
• Long-term maintenance on protein C replacement becomes increasingly expensive and difficult as the child grows 1
• Long-term high-intensity anticoagulation carries significant bleeding risks 1

For Heterozygous Protein C Deficiency

Routine prophylactic anticoagulation is NOT recommended in asymptomatic individuals without prior VTE 2:

• Heterozygotes may never experience thrombotic complications—in one family study, only 2 of 16 protein C deficient members had thromboembolic disorders 6
• Thromboembolic complications in childhood are rare and not obligatory in adults 6

For symptomatic patients with prior VTE:

• Standard oral anticoagulation with vitamin K antagonist or heparin therapy remains standard 7
• Either LMWH or VKAs can be used for symptomatic DVT or PE, with decision based on patient values, resources, infrastructure, and comorbidities 1
• For warfarin: INR monitoring 2-3 times weekly until stable therapeutic range (2.0-3.0), then weekly, eventually every 4 weeks once stable 8
• For DOACs: annual renal function assessment, medication adherence checks, and bleeding risk reassessment 8

Pregnancy and Postpartum Management

Postpartum prophylaxis with LMWH for 6 weeks is strongly recommended for patients with protein C deficiency and positive family history of VTE 8:

• The postpartum period carries high thrombotic risk 8
• Avoid estrogen-containing contraceptives and hormone replacement therapy, which synergistically increase thrombotic risk 8

Monitoring and Prevention

Perioperative Management

• Protein C replacement is used for prevention of thrombotic complications around surgery in severe protein C deficiency 4
• Prophylaxis for DVT is recommended in hospitalized patients with acute medical conditions 9

Risk Factor Modification

• Avoid prolonged immobilization 9
• Manage infection and medical comorbidities that increase DVT risk 9
• Patients with history of venous insufficiency are at higher risk of developing subsequent DVT 9

Surveillance for Acute DVT

If unilateral acute edema, leg pain, or localized heat develops, use duplex ultrasound to rule out acute DVT 9:

• If DVT is ruled out but clinical suspicion remains high, consider CT pulmonary angiography to exclude pulmonary embolism 8

Common Pitfalls to Avoid

• Never start warfarin without heparin coverage in protein C deficiency—this causes paradoxical thrombosis and skin necrosis 2, 5
• Do not use adult reference ranges for pediatric patients—protein C levels vary significantly with age 3
• Avoid testing during acute thrombosis or on anticoagulation—vitamin K antagonists and liver disease cause acquired deficiency 3
• Do not assume all heterozygotes need lifelong anticoagulation—many remain asymptomatic throughout life 3, 6
• Recognize that partially clotted samples falsely raise chromogenic PC levels but reduce clotting-based assay levels 3