Hemostasis and Thrombosis

• Major components of hemostasis:

  • Primary hemostasis (platelet plug)

    • Defects lead to mucosal bleeding (petechiae, purpura, epistaxis)

  • Secondary hemostasis (blood clot)

    • Defects lead to larger bleeds related to surgery/trauma (joint bleeds, muscle bleeds)

• Coagulation Cascade:

  • Intrinsic pathway

    • Initiated by Factor XII → activates prekallikrein to kallikrein and high-molecular-weight kininogen → activation of factor XI and IX and VIII

  • Extrinsic pathway

    • Initiated by tissue factor → activate factor 7

  • Common pathway

    • Factor X, V, II and I (symmetrical roman numerals)

• Vitamin K dependent factors:

  • Factor II, VII, IX, X, protein C and S

  • Inhibited by warfarin

  • All produced in liver

• Natural anticoagulants:

  • Antithrombin

  • Protein C and Protein S

  • Tissue factor pathway inhibitor (TFPI)

• Individual factor clinical pearls:

  • Factor XIII deficiency:

    • Does not affect INR and PTT

  • Factor XII deficiency:

    • May affect PTT in vitro but no clinical bleeding, does not require treatment

  • Factor XI deficiency:

    • Mild to no bleeding- May present late in life

  • Factor VIII, IX deficiency:

    • Hemophilia A & B

    • May require recombinant/activated factor VIII, IX or downstream product

  • Factor VII deficiency:

    • Rare autosomal recessive

    • Affects PT/INR, not PTT

    • Treated with recombinant factor VIIa q6-8h or FFP

  • If both INR and PTT affected: think something in the common pathway

    • X, V, II, I, or fibrinogen

      • Acquired factor X deficiency is associated with AL amyloidosis

  • If acquired inhibitor present:

    • Most likely would require some type of immune suppression such as corticosteroids, IVIG, Rituximab, cyclosporine, PLEX, etc. 

• Fibrinolysis & clot degradation:

  • Plasminogen activators

    • Convert plasminogen to plasmin, which degrades fibrin clots

    • Mechanism of action of tPA (tissue plasminogen activator)

Antithrombotic/Anticoagulants

• Vitamin K antagonist

  • Warfarin:

    • Competitively inhibits vitamin K oxide reductase

    • Prevents carboxylation of Gla residues on their amino terminus

    • Hepatic clearance

    • Main indications:

      • anticoagulation for mechanical heart valves

      • Antiphospholipid syndrome (APLS)

    • Administration requires close monitoring of INR

    • Rare side effect is warfarin skin necrosis

      • Due to hypercoagulable state within 24 hours of warfarin treatment

      • Due to shorter half life of protein C which leads to thrombotic state

      • Deficiency of protein C and S, Factor V Leiden, antithrombin III, hyperhomocysteinemia, and antiphospholipid antibodies are common risk factors

    • Reversible with:

      • Hold medication

        • If INR < 10, no bleeding

      • Vitamin K

        • If INR > 10, no bleeding

      • FFP is technically an option

      • PCC (preferred in emergent situations)

• Antithrombin activation

  • Heparin

    • Hepatic clearance

    • Reversible with protamine sulfate

  • Lovenox

    • More specific to target factor Xa activity

    • Renal clearance

    • Reversible with protamine sulfate

  • Fondaparinux

    • More specific to target factor Xa activity 

    • Renal clearance

    • NOT reversible with protamine sulfate

• Factor Xa inhibitor

  • Apixaban, Edoxaban, Betrixaban

  • Antidote: Andexanet Alpha

• Direct Thrombin inhibitors

  • Argatroban

    • Hepatic clearance

    • Non-peptide 

    • Parenteral 

  • Bivalirudin

    • Renal clearance

    • Peptide (20 aa)

    • Parenteral 

  • Dabigatran (Pradaxa)

    • Oral 

    • Renal clearance

    • Antidote: Idarucizumab 

Antiplatelets

• COX inhibitor

  • Aspirin

    • Irreversible platelet inhibitor

    • Acetylates cyclooxygenase 1 & 2

    • Commonly used in cardiac/stent patients

• P2Y12 Antagonists (ADP receptor)

  • Ticlopidine, clopidogrel, prasugrel, ticagrelor

    • Commonly used in cardiac/stent patients

• GPIIB/IIIa antagonists

  • Has indication in ACS with PCI but not widely used

  • Can cause rapid thrombocytopenia (drug/platelet complex leads to ab formation)

  • Abciximab

    • Half life 14 days

  • Eptifibatide 

    • Cyclic heptapeptide

    • Very short half life <1 hour

  • Tirofiban

• Protease activated receptor 1 (PAR1)

  • Vorapaxar

    • Irreversible 

    • Used to reduce thrombotic cardiovascular events in MI and PAD (secondary prevention)

    • Cleared in feces and renally

Von Willebrand Disease (VWD)

• Von Willebrand Factor:

  • Found in endothelial surface

  • Binds with GP1b on platelets

• Subtypes of vWD:

  • Type 1 and Type 3:

    • Quantitative disorders

    • Function proportional to level of enzyme/protein present

    • Type 1C:

      • Associated with increased clearance/shorter half life of vWF

  • Type 2:

    • Functional disorder/ Function is disproportion to level of enzyme/protein present

    • Type 2A:

      • Reduction/absence of high-molecular-weight vWF multimers → decreased platelet-dependent vWF activity

      • Heyde syndrome: Aortic stenosis + intestinal angiodysplasia + Type 2A vWD

    • Type 2B:

      • Gain-of-function mutation in vWF → increases its affinity for platelets → enhanced platelet binding and clearance → thrombocytopenia

      • The only one with elevated Ristocetin-Induced Platelet Aggregation (RIPA)

      • Autosomal dominant

      • Never give ddAVP

    • Type 2M:

      • Decreased vWF interactions with platelets/collagen but with a preserved multimer pattern

    • Type 2N:

      • Reduced binding of vWF to factor VIII → low factor VIII levels

      • Like hemophilia (may have a female patient to delineate from hemophilia)

        • The presence of a female patient with a hemophilia-like bleeding phenotype should prompt consideration of vWD rather than hemophilia.

	FVIII:C	vWF:Ag	vWF: RCoF	RIPA
Type 1 (most common)	↓	↓	↓	↓ or normal
Type 2A	↓	↓	↓↓	↓↓
Type 2B	↓	↓	↓↓	↑
Type 2N (recessive)	↓↓	normal	normal	normal
Type 3 (rare, recessive)	↓↓↓	↓↓↓	↓↓↓	↓↓↓

Treatment: Depends on type of vWD

• Desmopressin (ddAVP)

  • Transiently increases vWF and FVIII in plasma

  • Used in: Type 1 and Type 2A (minor procedures)

  • Administered nasally or IV

    • Ideally can perform a challenge to document response (pre, 1hr, 4 hr levels)

  • Hyponatremia can occur (from SIADH)

  • Development of tachyphylaxis after a few doses

• Intermediate-purity factor concentrates

  • Humate-P

  • Alphanate

  • Wilate

• Recombinant vWF

  • Does NOT contain factor 8, therefore not for acute bleed in Type 3

  • Indications:

    • Moderate/severe Type 1 for major procedures

    • Type 2A for major procedures

    • Type 2B for most procedures

• Antifibrinolytics

  • Tranexamic acid

  • Aminocaproic acid

Pregnancy:

• Normally one can expect physiologic increase in vWF during pregnancy that exceeds 50IU/dL

• Should be above 50IU/dL for epidural to be placed or surgery/delivery (and for 3-5 days after delivery)

• vWF levels also decline over 2-3 weeks postpartum

Acquired von Willebrand disease:

• Associated with certain lymphoproliferative disorders, plasma cell dyscrasias, neoplasms, severe thrombosis, hypothyroidism, ECMO/LVAD

• Treatment:

  • Desmopressin, factor VIII/vWF concentrates, IVIG, plasmapheresis, plateletpheresis, corticosteroids, rituximab, other types of immunosuppression

Hemophilia

• X-linked recessive

• Deficiency of factor VIII (type A) and factor IX (type B)

  • Levels correlate with bleeding severity

    • Severe: <1%

      • Spontaneous bleeding, risk of intracranial bleeding, risk of developing inhibitors

    • Moderate: 1-5%

      • Fewer spontaneous bleeds, but can become severe once bleed starts

    • Mild: 5-50%

      • Bleeding with certain procedures (surgery/trauma), catastrophic bleeding is rare

• Lead to larger bleeds related to surgery/trauma (joint bleeds, muscle bleeds), intracranial

  • Can lead to compartment syndrome

  • Long term sequelae:

    • Hemophilic arthropathy

      • Decreased joint space

      • Bony erosion

• Treatment:

  • Factor therapy

    • Raise levels to normal for severe bleeds or treat minor bleeds

      • Goal: above 50%

  • Factor VIII

    • 1 unit/kg body weight raises factor level 2%

      • Example: 50 U/kg raises level to 100%, followed by maintenance 25 U/kg in 12 hours

  • Factor IX

    • 1 unit/kg body weight raises factor level 1%

      • Ex: 100 U/Kg raises level to 100%, followed by maintenance 50 U/Kg

  • Use Aminocaproic acid (Amicar) or TXA for mucosal/oral cavity bleeding

  • Consider DDAVP for mild hemophilia A

  • Emicizumab: (factor 8 mimetic)

    • approved for prophylaxis of bleeding in congenital hemophilia A

    • Associated with thrombotic complications when used with FEIBA

  • Gene therapy is also an option for hemophilia A and B

  • Bypassing agents are useful in factor deficiencies, particularly with inhibitors

    • Be suspicious of an inhibitor if bleeding does not resolve with factor replacement

Hypercoagulability

• Who needs a work up?

  • DVT/PE with intermediate risk of recurrence

  • Unprovoked VTE in unusual locations

    • Cerebral vein/sinus, retinal vein/artery, splanchnic veins, renal veins, gonadal vein, skin

    • Arterial thrombus (if unexplained)

• Timing of testing should be at least 1 month after being off of anticoagulation

  • Do not test during acute clot as it can skew test results/difficult to interpret

Thrombophilias:

• Antiphospholipid syndrome

  • Needs history of thrombosis and/or pregnancy morbidity

  • Labs tested need to be down 2 times > 12 weeks apart

    • Anti-cardiolipin (IgG/IgM)

    • Anti-beta2-glycoprotein (IgG/IgM)

    • Lupus anticoagulant

      • Strongest independent factor

      • Can be falsely positive if drawn while on anticoagulation

  • Treatment: Warfarin

• Antithrombin deficiency

• Protein C & S deficiency

• Homozygous Factor V Leiden (most common)

• Homozygous Prothrombin gene mutation (factor II)

• Heterozygous for both F5L and prothrombin gene

• Hemolytic diseases