Hypercoagulable States

Autoantibodies that bind to phospholipid-binding proteins on cell surfaces trigger prothrombotic state through endothelial activation, platelet aggregation, and complement activation.

Clinical Features

• Venous and arterial thrombosis.
• Recurrent pregnancy loss.
• Can be associated with SLE vs primary disorder.
• Rapid multiorgan thrombosis (think about Catastrophic APS but also consider TTP, HUS, DIC).

Diagnosis

• Requires clinical criteria plus laboratory criteria (present on two occasions ≥ 12 weeks apart).
• Lupus anticoagulant.
• Anticardiolipin antibody.
• Anti-β2 glycoprotein I antibody.
• TTE if structural disease suspected.
• Ambulatory cardiac monitoring if frequently symptomatic.

Management

• Venous thrombosis: indefinite warfarin (INR 2–3).
• Arterial thrombosis: warfarin ± aspirin.
• Consider aspirin for primary prevention in high-risk patients.
• Hydroxychloroquine in SLE-associated APS.
• Heparin gtt, steroids, PLEX, and/or IVIG for catastrophic APS.
• Avoid DOACs in triple-positive APS.

Catastrophic APS (CAPS)

Presentation 

• Rapid Onset: Thrombosis in ≥3 organs, systems, or tissues within a week.
• Common Sites:
  • Kidneys (renal failure, hypertension).
  • Lungs (acute respiratory distress syndrome [ARDS], pulmonary embolism).
  • Brain (stroke, seizures, encephalopathy).
  • Heart (myocardial infarction, valve thrombosis).
  • Skin (livedo reticularis, purpura, necrosis).
  • Adrenals (adrenal insufficiency).
• Systemic Inflammatory Response: Fever, elevated inflammatory markers (e.g., CRP, ESR), often mimicking sepsis.
• Triggers: Identified in ~50% of cases—e.g., infection (most common), surgery, trauma, pregnancy, or anticoagulation withdrawal. 

Criteria for definite CAPS 

• Evidence of multi-organ involvement (3 or more)
  • Clinical or imaging evidence of thrombosis or dysfunction (e.g., CT/MRI showing stroke, renal infarcts).
• Confirmation by histopathology of small vessel occlusion
• Laboratory confirmation of aPL antibodies (detected on 2 occasions 12 weeks apart)
• Absence of alternative diagnoses (Exclude mimics like TTP, HUS, DIC or HIT)

Management 

• IV heparin and high dose steroids 
• For refractory cases: consider PLEX, IVIG, rituximab

Background

Type 1 (non-immune mediated, benign, direct heparin effect) vs. Type 2 (immune-mediated; IgG antibodies against platelet factor 4 (PF4)–heparin complexes à platelet activation, thrombocytopenia, and paradoxical thrombosis).

Type 2 HIT

Risk Factors: UFH > LMWH, surgical patients (especially orthopedic/cardiac), females, higher heparin doses.

• Key features:
  • Platelet drop ≥ 50%
  • Onset 5-14 days after first heparin exposure or within 24 hours if prior heparin exposure within 30–100 days (antibody persistence).

Thrombosis

• Venous (DVT, PE) > arterial (stroke, MI, limb ischemia).
• Unusual sites: adrenal vein (hemorrhage), skin necrosis at injection sites.
• Occurs in 30–50% of untreated cases; risk persists 4–6 weeks post-heparin cessation.

Symptoms

• Thrombosis-related (e.g., leg swelling, chest pain).
• Skin lesions (erythema, necrosis) in ~10%.
• Bleeding rare unless severe thrombocytopenia.

Evaluation

• Calculate 4T score for risk stratification (low, intermediate, high).
• If intermediate-high probability: stop heparin and send the following
  • Screening: Anti-PF4/heparin ELISA.
  • Confirmation: Serotonin release assay (will reflex to this if above test positive); >20% serotonin release confirms HIT.

Management

• Intermediate probability: Hold heparin, start non-heparin anticoagulant.
• High probability (~50%): Hold heparin, start non-heparin anticoagulan.
• Argatroban (direct thrombin inhibitor) for prophylaxis and treatment of thrombosis.
  • Avoid platelet transfusions as can increase thrombogenic effect.
  • Avoid warfarin until complete platelet recovery as may cause microthrombosis.
  • Hematology consult for all confirmed HIT.

Evaluation

• Screen with activated protein C resistance assay (Normal >2.0, heterozygotes 1.5-2.0, homozygotes <1.5).
• Confirmation with Factor V Leiden PCR.

Management

• VTE treatment same as general population.
• VTE 3-8x risk in heterozygotes; 9-18x increased risk in homozygotes.
• Avoid combined oral contraceptives/HRT; progestin-only options safer.

Evaluation

• PCR of G20210A mutation (2-4% prevalence).

Management

• VTE treatment same as general population.
• Extend anticoagulation for unprovoked/recurrent cases.
• Prophylaxis in high-risk settings for carriers.
• Avoid OCPs.

Key Features

• Autosomal dominant
• First event occurs between 10-50 years of age.
• Protein C: low in settings of thrombosis, DIC, nephrotic syndrome, intra/post-op. 
• Protein S: low in infectious (HIV) and autoimmune processes (IBD).
• Protein S decreases during pregnancy (decreased free protein S, normal total protein S).

Evaluation

• Functional Protein C and S assays.

Management

• VTE treatment same as general population.
• Avoid OCPs/HRT - High risk pts may require protein C concentrate prior to surgery.
• Increased risk of warfarin-induced skin necrosis (3-8 days following initiation).

Key Features

• Autosomal dominant with variable penetrance.
• Unprovoked VTE (DVT, PE) often <40–50 years; 50–70% lifetime risk by age 60.
• Unusual sites: Cerebral, mesenteric, portal vein thrombosis.
• Acquired deficiency can be caused by liver disease, nephrotic syndrome, DIC, or heparin therapy.

Evaluation 

• Functional antithrombin activity (AT-heparin cofactor assay).
• Then perform antigen quantity testing.

Management 

• VTE treatment same as general population.
• Indefinite anticoagulation for unprovoked cases.
• Prophylaxis in triggers.
• Antithrombin concentrate for severe/homozygous cases.