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Harrison's Section 3 - Haemostasis Disorders

Chapters 120-123: Complete Teaching Notes

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CHAPTER 120: Disorders of Platelets and Vessel Wall

The Foundation: Normal Haemostasis

• Released from megakaryocytes under flow in capillary sinuses
• Normal count: 150,000-450,000/μL
• Life span: 7-10 days
• ~1/3 of platelets reside in the spleen (splenic sequestration never drops count below ~40,000/μL no matter how large the spleen)
• Are physiologically very active but anucleate - cannot make new proteins

• Synthesized in the liver (also other organs)
• IL-6 stimulates synthesis (so levels rise with inflammation)
• Removed from circulation by binding to platelets/megakaryocytes - a feedback loop: fewer platelets → less TPO removed → TPO rises → more platelet production

1. Vascular injury exposes subendothelial collagen and von Willebrand factor (VWF)
2. Platelets adhere via VWF (primary bridge) and collagen
3. Adhesion generates intracellular signals → activates GpIIb/IIIa (αIIbβ3) receptor
4. GpIIb/IIIa mediates platelet-platelet aggregation
5. Activated platelets release granule contents: nucleotides, adhesive proteins, growth factors, procoagulants
6. This recruits more platelets → occlusive platelet thrombus
7. Simultaneously, the coagulation cascade generates fibrin to stabilize the plug

• Endothelium: 1-6 × 10¹³ cells, ~6 tennis courts of surface area
• Normally presents an antithrombotic surface
• Key: endothelium-derived vasodilators are also platelet inhibitors (e.g., nitric oxide)
• When injured, rapidly becomes prothrombotic: promotes coagulation, inhibits fibrinolysis, activates platelets

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Disorders of Platelets

THROMBOCYTOPENIA (Low Platelet Count)

• <100,000/μL - surgical bleeding risk increases
• <50,000/μL - moderate spontaneous bleeding risk
• <20,000/μL - spontaneous mucosal/CNS bleeding risk

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HEPARIN-INDUCED THROMBOCYTOPENIA (HIT)

• HIT Type 1 (non-immune): mild, transient, platelet count rarely <100k, benign, resolves with continued heparin - not clinically significant
• HIT Type 2 (immune-mediated): the dangerous one - discussed below

• Heparin binds to Platelet Factor 4 (PF4) → forms heparin-PF4 complex
• This complex is immunogenic → IgG antibodies form
• IgG-PF4-heparin complexes bind FcγRIIA receptors on platelets → platelet activation and aggregation
• Result: paradoxical thrombosis (the drug given to prevent clots causes clots!)
• Thrombocytopenia occurs because activated platelets are consumed

• Platelet count drops by >50% from baseline (or to <100k), typically 5-14 days after starting heparin
• Can occur earlier (within hours) in re-exposed patients
• Classic paradox: thrombocytopenia + thrombosis (not bleeding!)
• Both venous (DVT, PE) and arterial (limb ischemia, stroke, MI) thrombosis can occur
• Any heparin exposure counts: IV unfractionated, LMWH, heparin flushes, heparin-coated catheters

1. Stop ALL heparin immediately (including LMWH, flushes, heparin-coated catheters)
2. Start a non-heparin anticoagulant immediately (do not wait for thrombosis) - options: argatroban (direct thrombin inhibitor), fondaparinux, bivalirudin
3. Do NOT give platelet transfusions (can worsen thrombosis - "fuel on the fire")
4. Do NOT start warfarin until platelet count recovers (risk of venous limb gangrene from rapid protein C depletion)
5. Patient must never receive heparin again without careful reassessment

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IMMUNE THROMBOCYTOPENIC PURPURA (ITP)

• Autoimmune IgG antibodies against platelet surface glycoproteins (GpIIb/IIIa or GpIb/IX)
• Antibody-coated platelets destroyed in spleen (and liver) by macrophages
• TPO level often inappropriately low (bound to platelets)

• Acute ITP: children, often post-viral (esp. post-VZV or post-viral URI), self-limiting (80% resolve spontaneously in weeks-months)
• Chronic ITP: adults (especially women), persistent >12 months, rarely self-limiting

1. Observation if platelets >30k and no significant bleeding
2. Glucocorticoids (prednisone 1 mg/kg/d or dexamethasone 40 mg/d × 4 days) - first line
3. IVIG or anti-D immunoglobulin - for rapid response needed (surgery, severe bleeding)
4. TPO receptor agonists: romiplostim, eltrombopag - second-line, stimulate platelet production
5. Rituximab (anti-CD20): targets B cells producing antibodies
6. Splenectomy: durable remission in ~60-70% but reserved for refractory cases
7. Fostamatinib (Syk inhibitor) - newer option for refractory ITP

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THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)

1. Microangiopathic haemolytic anaemia (MAHA)
2. Thrombocytopenia
3. Neurological symptoms (confusion, seizures, stroke)
4. Renal insufficiency
5. Fever

• VWF is normally secreted as ultra-large multimers
• ADAMTS13 (a metalloprotease) cleaves these ultralarge VWF multimers into smaller, less "sticky" forms
• In TTP: ADAMTS13 is deficient (congenital = Upshaw-Schulman syndrome) or destroyed by autoantibodies (idiopathic TTP)
• Result: ultralarge VWF persists → pathologic platelet adhesion/aggregation → microthrombi in microvasculature → platelet consumption + shearing of RBCs (schistocytes) → MAHA
• ADAMTS13 activity <10% is diagnostic of TTP

• Low platelets, elevated LDH, elevated bilirubin (indirect), low haptoglobin
• Schistocytes (helmet cells, fragmented RBCs) on peripheral smear - the hallmark
• Normal PT and aPTT (differentiates from DIC!)
• Direct antiglobulin test (Coombs) negative (differentiates from autoimmune haemolytic anaemia)

• More common in women
• More common in HIV infection and pregnancy
• Drug-induced MAHA: ticlopidine/clopidogrel (antibody-mediated); cyclosporine, tacrolimus, gemcitabine, mitomycin C (direct endothelial toxicity)

1. Therapeutic Plasma Exchange (TPE) - the cornerstone; replaces ADAMTS13 and removes antibodies; continue until platelet count normal and haemolysis resolved ≥2 days
2. Glucocorticoids - adjunct (never sole treatment), reasonable despite lack of RCT evidence
3. Rituximab - added to initial therapy to decrease relapse risk
4. Caplacizumab - anti-VWF nanobody (blocks interaction between ultralarge VWF and platelets); decreases mortality and burden of care when ADAMTS13 <10%; start alongside TPE and rituximab
5. No platelet transfusions (worsen microthrombosis)

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HEMOLYTIC-UREMIC SYNDROME (HUS)

• Classic (D+) HUS: Shiga toxin-producing E. coli O157:H7 (or O104:H4); follows bloody diarrhoea in children; predominantly renal failure; self-limiting
• Atypical HUS: complement dysregulation (mutations in Factor H, Factor I, MCP); worse prognosis; treat with eculizumab (anti-C5 complement inhibitor)
• ADAMTS13 levels are NORMAL in HUS (key distinction from TTP)

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THROMBOCYTOSIS

• Reactive (secondary): most common; due to iron deficiency, infection, inflammation, post-splenectomy; no treatment of the platelet count needed
• Primary (essential thrombocythaemia): clonal myeloproliferative neoplasm; treated if symptomatic or high risk

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QUALITATIVE PLATELET DYSFUNCTION

• Glanzmann thrombasthenia: absent/dysfunctional GpIIb/IIIa → failure of platelet aggregation; normal count, prolonged bleeding time; treat with platelet transfusion, recombinant FVIIa
• Bernard-Soulier syndrome: absent/dysfunctional GpIb/IX → failure of platelet adhesion (GpIb is the VWF receptor); giant platelets on smear; mild thrombocytopenia
• Storage pool disorders: deficient dense granules (delta) or alpha granules; mild-moderate bleeding

• Aspirin/NSAIDs: irreversible COX-1 inhibition → decreased thromboxane A2
• Uremia: platelet dysfunction corrected by dialysis, DDAVP, conjugated oestrogens, cryoprecipitate (VWF)
• Myeloproliferative disorders, paraproteinaemias

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VON WILLEBRAND DISEASE (vWD)

1. Platelet adhesion bridge (GpIb-VWF-collagen)
2. Carrier protein for Factor VIII (protects FVIII from degradation - explains why FVIII levels are low in VWD)

• Prolonged bleeding time / abnormal PFA-100
• Prolonged aPTT (mild-moderate in type 1, significant in type 3)
• Normal PT
• Reduced VWF antigen (VWF:Ag), reduced VWF activity (VWF:RCo = ristocetin cofactor activity), reduced FVIII activity

• DDAVP (desmopressin): releases stored VWF from endothelial Weibel-Palade bodies; works for Type 1 and some Type 2; give before procedures; intranasal or IV
• VWF concentrates (plasma-derived or recombinant): for Types 2 and 3, major surgery, DDAVP failures
• Antifibrinolytics (tranexamic acid, epsilon-aminocaproic acid): adjunct for mucosal bleeding, dental procedures

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DISORDERS OF THE VESSEL WALL

• Henoch-Schönlein Purpura (IgA vasculitis): IgA deposition in small vessels; palpable purpura on lower extremities/buttocks, arthritis, abdominal pain, glomerulonephritis; usually self-limiting
• Hereditary Haemorrhagic Telangiectasia (HHT/Osler-Weber-Rendu): AD; mutations in endoglin or ALK1; mucocutaneous telangiectasias, recurrent epistaxis, AVM (lung, liver, CNS)
• Ehlers-Danlos syndrome: connective tissue disorder; vascular type (Type IV) - life-threatening; due to collagen defects
• Scurvy (Vitamin C deficiency): perifollicular haemorrhages; impaired collagen synthesis in vessel wall
• Senile purpura: loss of dermal connective tissue support; easy bruising on sun-exposed skin in elderly

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CHAPTER 121: Coagulation Disorders

The Coagulation Cascade - Your Foundation

• Extrinsic pathway (TF/FVII): triggered by tissue factor exposure; monitored by PT
• Intrinsic pathway (FXII → FXI → FIX → FVIII): contact activation; monitored by aPTT
• Common pathway: FX → FV → prothrombin → thrombin → fibrinogen → fibrin
• Important: FXII deficiency prolongs aPTT but causes NO bleeding (redundant activation paths)

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Rare Clotting Factor Deficiencies (Table 121-1 summary)

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HEMOPHILIA A AND B

• Hemophilia A: FVIII deficiency (1 in 5,000 males)
• Hemophilia B: FIX deficiency / Christmas disease (1 in 30,000 males)
• Female carriers: may have mildly reduced factor levels; can bleed (especially if lyonization is extreme)

• Hemarthroses (commonest): knees, elbows, ankles; acute pain/swelling; chronic repeated bleeding → hemophilic arthropathy (joint destruction)
• Muscle hematomas: iliopsoas hematoma can cause femoral nerve palsy, hip pain mimicking appendicitis
• Intracranial hemorrhage: most feared complication; treat any head trauma immediately without waiting for CT
• Pseudotumors: encapsulated hematomas, can erode bone

• Prolonged aPTT, normal PT
• Specific factor assay: FVIII or FIX level
• Screen for inhibitors: Bethesda assay

• FVIII concentrates for Hemophilia A; FIX concentrates for Hemophilia B
• Recombinant products preferred (lower infection risk)
• Dose calculation:
  • FVIII: 1 unit/kg raises FVIII by ~2%; half-life 8-12 h
  • FIX: 1 unit/kg raises FIX by ~1%; half-life 18-24 h
• For hemarthrosis: aim for 30-50% levels
• For major surgery/life-threatening bleed: aim for >80-100% levels

• DDAVP (desmopressin): releases stored FVIII from endothelial cells; only works in mild Hemophilia A; not for Hemophilia B
• Antifibrinolytics (tranexamic acid): adjunct, especially for mucosal bleeding; avoid in hematuria
• Emicizumab (Hemlibra): bispecific antibody that bridges FIXa and FX (mimics FVIIIa cofactor activity); subcutaneous; works even in patients with FVIII inhibitors; game-changing therapy
• Gene therapy: increasingly available; AAV-based vectors; can achieve long-term near-normal factor levels

• Inhibitors (alloantibodies): develop in ~30% of severe Hemophilia A patients, ~3-5% of Hemophilia B
  • Low-titer inhibitors (<5 Bethesda units): may respond to high-dose factor replacement
  • High-titer inhibitors: use bypassing agents: recombinant FVIIa (NovoSeven) or activated PCC (aPCC/FEIBA); OR emicizumab
  • Immune tolerance induction (ITI): daily high-dose FVIII infusions to eradicate inhibitor
• Blood-borne infections: historical issue; HCV, HIV in patients treated pre-1985; now minimized with recombinant products and viral inactivation
• Joint disease: hemophilic arthropathy requires joint replacement in severe cases; prophylactic factor replacement prevents joint damage

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FACTOR XI DEFICIENCY (Hemophilia C)

• AR inheritance; highest prevalence in Ashkenazi Jewish population (1 in 450)
• Mild to moderate bleeding phenotype; poor correlation of factor level with bleeding severity
• Bleeding mainly post-trauma or surgery (especially at sites high in fibrinolytic activity: oral cavity, urogenital tract, ENT)
• Very rare spontaneous hemarthroses (distinguishes from Hemophilia A/B)
• Lab: Prolonged aPTT, normal PT
• Treatment: FFP or FXI concentrate (half-life 40-70 h, give every other day); antifibrinolytics; rFVIIa for inhibitor patients
• Low-dose rFVIIa (10-15 μg/kg) + antifibrinolytic before surgery avoids plasma products

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RARE BLEEDING DISORDERS

• Bleeding severity correlates with factor type: FXIII and FX deficiency → severe/life-threatening; FVII and dysfibrino-genemia → often mild
• Hallmarks of these disorders: mucosal bleeding and umbilical stump bleeding (not hemarthroses)
• FVII deficiency: increased in Ashkenazi Jews; treat with rFVIIa
• FX deficiency: associated with primary amyloidosis (amyloid absorbs FX)
• FXIII deficiency: unique lab profile - normal PT/aPTT; check urea clot solubility test; delayed re-bleeding from wounds

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FAMILIAL MULTIPLE COAGULATION DEFICIENCIES

• Mutations in LMAN1 (Golgi chaperone protein) or MCFD2 (cofactor for LMAN1)
• Both FV and FVIII are ~5% activity
• Mild bleeding despite double deficiency
• Treatment: FFP (for FV) + DDAVP or FVIII concentrate (for FVIII)

• Mutations in genes encoding GGCX (gamma-glutamyl carboxylase) or VKORC1 (vitamin K epoxide reductase complex)
• All VitK-dependent factors low: FII, FVII, FIX, FX (procoagulant) AND proteins C and S (anticoagulant)
• Treat with high-dose vitamin K; bleeding treated with FFP/PCCs

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DISSEMINATED INTRAVASCULAR COAGULATION (DIC)

• Consumption of clotting factors and platelets → bleeding
• Microthrombi in microvasculature → organ failure (MAHA)
• Secondary hyperfibrinolysis → further bleeding

1. Sepsis (esp. gram-negative; endotoxin activates TF pathway)
2. Obstetric complications (abruption, amniotic fluid embolism, retained dead fetus, eclampsia)
3. Malignancy (AML M3/APL releases granules with TF; mucin-secreting adenocarcinomas)
4. Massive trauma/burns (tissue TF release)

• Low fibrinogen
• Low platelets
• Prolonged PT and aPTT
• Elevated D-dimer (fibrin degradation products)
• Elevated FDPs
• Schistocytes on smear
• Low antithrombin

• Treat the underlying cause - this is paramount
• Replace what is consumed: FFP (factors), cryoprecipitate (fibrinogen + FVIII + VWF), platelets
• Maintain fibrinogen >150 mg/dL, platelets >50k for active bleeding
• Heparin: controversial; may be considered in DIC with predominantly thrombosis (e.g., purpura fulminans, arterial/venous thrombosis) but avoid in DIC with hemorrhage

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ACQUIRED COAGULATION INHIBITORS

• Autoantibodies against FVIII
• May be idiopathic, or associated with: malignancy, autoimmune disease, pregnancy, drugs
• Presents with sudden severe bleeding in a patient with no prior bleeding history
• Lab: prolonged aPTT that does NOT correct on mixing study (inhibitor pattern vs. factor deficiency which DOES correct)
• Treatment: bypassing agents (rFVIIa or aPCC) + immunosuppression (glucocorticoids + rituximab +/- cyclophosphamide)

• Antiphospholipid antibodies that paradoxically prolong aPTT in vitro but cause thrombosis in vivo
• dRVVT and hexagonal-phase phospholipid test: positive in lupus anticoagulant (negative in acquired inhibitors)
• Lupus anticoagulant appears to inhibit multiple factors in vitro (FVIII, FIX, FXI, FXII) - distinguish from specific acquired inhibitor which is factor-specific
• Rare exception: antibodies to prothrombin in antiphospholipid syndrome → hypoprothrombinemia → actual bleeding

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COAGULATION DISORDERS IN LIVER DISEASE

• The liver synthesizes almost ALL clotting factors (except FVIII and VWF, which also come from endothelium)
• Liver also synthesizes anticoagulant proteins C and S and antithrombin
• Therefore, liver disease causes a "rebalanced" haemostasis (loss of both pro- and anti-coagulant factors)
• Clinical implications: bleeding AND thrombosis both occur; the INR/PT may be misleadingly high without reflecting true bleeding risk
• Specific issues: low fibrinogen (impaired synthesis), hyperfibrinolysis, thrombocytopenia (splenomegaly + reduced TPO)
• Treatment: vitamin K (if prolonged PT and adequate liver function); FFP; cryoprecipitate; platelet transfusion; tranexamic acid; avoid over-correction

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CHAPTER 122: Arterial and Venous Thrombosis

Overview of Thrombosis

"Thrombosis is haemostasis at the wrong place and at the wrong time" - MacFarlane

1. Endothelial injury/dysfunction
2. Hypercoagulability
3. Stasis (reduced flow)

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Arterial vs. Venous Thrombosis - Key Differences

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Risk Factors for Venous Thromboembolism (VTE)

• Major surgery (orthopedic, abdominal, neurological) - highest surgical risk
• Malignancy: 4-fold increase; cancer + VTE = reduced survival
• Pregnancy/postpartum: relative risk 4.3; absolute risk 199.7/100,000 woman-years
• OCP/HRT: estrogen increases hepatic synthesis of clotting factors
• Immobilization/bedrest
• Long-haul flights (>4 hours doubles risk; absolute risk still low: 1 in 6000)
• Obesity, older age
• COVID-19: ~20% of hospitalized patients had coagulation abnormalities + PE/DVT
• Prior VTE: strongest predictor of recurrence

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Genetics and Pharmacogenomics

• Clopidogrel is a prodrug requiring hepatic conversion by CYP2C19 (and CYP3A4)
• Loss-of-function CYP2C19*2 allele → reduced active metabolite → inadequate platelet inhibition → higher cardiovascular events
• Up to 25% of patients may be affected
• Current guidance: CYP2C19 genotyping may guide ADP antagonist selection in high-risk PCI patients (use prasugrel or ticagrelor instead)

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Fibrinolysis and Thrombosis

• PAI-1 (plasminogen activator inhibitor-1): the main inhibitor of tPA; 4G/5G polymorphism at -675 affects PAI-1 levels
• Elevated PAI-1 → impaired fibrinolysis → thrombosis risk
• Lipoprotein(a) [Lp(a)] mimics plasminogen but cannot be activated → competes with plasminogen → impairs fibrinolysis → thrombosis risk
• Elevated homocysteine: damages endothelium, activates coagulation, impairs fibrinolysis

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CHAPTER 123: Antiplatelet, Anticoagulant, and Fibrinolytic Drugs

The Big Picture

1. Antiplatelet drugs - primarily for arterial thrombosis
2. Anticoagulants - primarily for venous thrombosis (and AF/valve disease)
3. Fibrinolytics - dissolve established clots (STEMI, massive PE, stroke)

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ANTIPLATELET DRUGS

Aspirin

• Mechanism: Irreversibly acetylates COX-1 (and COX-2) → blocks conversion of arachidonic acid to thromboxane A2 (TXA2) → reduces platelet activation and vasoconstriction
• Irreversible for platelet lifetime (7-10 days); platelets cannot make new COX (anucleate)
• Low-dose (75-100 mg) sufficient for antiplatelet effect; higher doses inhibit endothelial COX-2 → loss of prostacyclin (antiplatelet) → counterproductive
• Aspirin resistance: Variable; likely multifactorial; no reliable clinical test; no standard genotyping indication currently
• Uses: MI, stroke, PCI, PAD, ACS
• Side effects: GI bleeding, peptic ulceration; bronchoconstriction in aspirin-sensitive asthma

ADP Receptor Antagonists (P2Y12 Inhibitors)

• Dual antiplatelet therapy (DAPT = aspirin + P2Y12 inhibitor) is standard for ACS and PCI
• Duration depends on stent type and bleeding risk
• For non-cardioembolic stroke/TIA: clopidogrel or ticagrelor + aspirin for 21-30 days, then aspirin alone

GpIIb/IIIa Inhibitors

• Block the final common pathway of platelet aggregation
• Abciximab (monoclonal antibody Fab fragment), Eptifibatide (cyclic peptide), Tirofiban (non-peptide)
• IV only; used during high-risk PCI
• Risk: significant bleeding; thrombocytopenia (immune-mediated with abciximab)

Phosphodiesterase Inhibitors

• Dipyridamole: inhibits PDE → increases cAMP/cGMP → inhibits platelet activation; also blocks adenosine uptake; used in combination with aspirin for secondary stroke prevention (Aggrenox)
• Cilostazol: PDE3 inhibitor; also vasodilator; used for peripheral arterial disease/intermittent claudication; contraindicated in heart failure

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ANTICOAGULANTS

Unfractionated Heparin (UFH)

• Binds antithrombin (AT) → conformational change → AT irreversibly inhibits thrombin (IIa) and Factor Xa (and IXa, XIa, XIIa)
• For thrombin inhibition: heparin must bind BOTH AT and thrombin (requires chains ≥18 saccharides)
• For Xa inhibition: heparin only needs to bind AT (shorter chains can do this)

• Binds to many plasma proteins (variable anticoagulant response → must monitor)
• PF4 (from activated platelets) neutralizes heparin → limited in platelet-rich arterial thrombi
• Monitoring: aPTT (target 2-3x normal) or anti-Xa level (0.3-0.7 units/mL)
• "Heparin resistance": >35,000 units/day to achieve therapeutic aPTT → elevated acute-phase proteins (fibrinogen, FVIII) shorten aPTT without affecting anti-Xa → use anti-Xa monitoring

• Prophylaxis: 5,000 units SC 2-3x daily (no monitoring needed)
• Treatment (VTE): bolus 5,000 units or 80 units/kg IV, then 18 units/kg/h
• Treatment (ACS): bolus 70 units/kg, then 12-15 units/kg/h

• Bleeding
• HIT (discussed above)
• Osteoporosis (long-term use)
• Hypoaldosteronism (hyperkalaemia)

Low Molecular Weight Heparin (LMWH)

• Produced by depolymerization of UFH; smaller chains (mean 4,500-5,000 Da vs. UFH 15,000 Da)
• Preferentially inhibits Factor Xa over thrombin (chains too short to bridge AT and thrombin)
• Advantages over UFH:
  • More predictable pharmacokinetics (SC bioavailability ~90%; UFH SC ~30%)
  • Less protein binding → predictable dose-response
  • Twice or once daily SC dosing; no routine monitoring needed
  • Lower risk of HIT (less PF4 binding)
• Monitoring required in: renal impairment (accumulates), obesity, pregnancy → measure anti-Xa levels (target 0.5-1.0 for BID dosing)
• Reversal: Protamine 60-80% effective
• Examples: Enoxaparin, dalteparin, tinzaparin

Fondaparinux

• Synthetic pentasaccharide; the minimal structure needed for AT binding
• Purely anti-Xa (too short to bridge AT and thrombin)
• No HIT (does not bind PF4; does not activate platelets)
• Once daily SC; renal excretion; no reversal agent
• Uses: DVT/PE prophylaxis, ACS, HIT (as non-heparin anticoagulant)

Direct Thrombin Inhibitors (DTIs)

• DTIs inhibit thrombin directly (no AT required)
• Inhibit both free and clot-bound thrombin (heparin/LMWH can only inhibit free thrombin)
• Argatroban: hepatically cleared → safe in renal failure; used for HIT
• Bivalirudin: renally cleared; bivalent (reversible) DTI
• Dabigatran: oral; 80% renally cleared → avoid in severe renal failure; reversal with idarucizumab (monoclonal Ab fragment)

Direct Oral Anticoagulants (DOACs) - Factor Xa Inhibitors

• Direct inhibitors of Factor Xa; do not require AT
• No routine monitoring (predictable PK/PD)
• Andexanet alfa: recombinant FXa decoy; reverses FXa inhibitors and LMWH
• Ciraparantag (PER977): universal reversal agent (investigational; binds UFH, LMWH, fondaparinux, DTIs, FXa inhibitors)
• Key clinical pearl: Low-dose rivaroxaban (2.5 mg BID) + aspirin reduces recurrent ischemic events in stable coronary or peripheral artery disease (COMPASS trial)

Warfarin (Vitamin K Antagonist)

• Inhibits vitamin K epoxide reductase (VKORC1) → blocks recycling of oxidized vitamin K → depletes reduced (active) vitamin K
• Result: reduced gamma-carboxylation of VitK-dependent factors (II, VII, IX, X, and Protein C, Protein S)
• FVII has the shortest half-life → PT prolonged first; protein C also has short half-life → transient hypercoagulable state at initiation

• Target INR 2-3 for most indications (AF, VTE, mechanical valve - bioprosthetic)
• Target INR 2.5-3.5 for mechanical mitral valve or double valve

• Vitamin K (phytonadione): oral (24-48h) or IV (hours); for non-urgent reversal
• 4-factor PCC (prothrombin complex concentrate): fastest reversal; immediate; contains FII, VII, IX, X; preferred for life-threatening bleeding
• FFP: slower (large volumes); use if PCC unavailable
• Recombinant FVIIa: off-label; partial reversal

• VKORC1 polymorphisms: affect sensitivity to warfarin (AA haplotype = more sensitive → lower dose needed)
• CYP2C9 polymorphisms: affect warfarin metabolism (poor metabolizers need lower doses)
• Genotype-guided dosing algorithms exist but clinical utility varies

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FIBRINOLYTIC DRUGS

• Ischemic stroke: tPA within 4.5 hours of onset (or within 3 hours for >80y, prior stroke+DM, on anticoagulants, NIHSS >25, large infarct on imaging)
• STEMI: if primary PCI not available within 120 min; tenecteplase preferred
• Massive PE with hemodynamic compromise
• Catheter-directed thrombolysis for extensive DVT

• Prior intracranial hemorrhage
• Recent (within 3 months) ischemic stroke
• Intracranial neoplasm, AVM, aneurysm
• Active internal bleeding (not menstruation)
• Suspected aortic dissection
• Recent (within 3 months) severe head trauma or brain/spinal surgery

• Bleeding - most common; intracranial hemorrhage (~0.5-1% with tPA for stroke)
• Reperfusion injury (myocardial)
• Anaphylaxis (streptokinase)

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Quick Clinical Integration: Approach to the Bleeding Patient

• Petechiae/purpura, mucosal bleeding, menorrhagia → platelet/vessel wall disorder (primary haemostasis)
• Deep tissue bleeding (joints, muscles, retroperitoneum), delayed re-bleeding → coagulation factor deficiency (secondary haemostasis)

• CBC + peripheral smear
• PT (extrinsic/common pathway)
• aPTT (intrinsic/common pathway)
• Thrombin time (fibrinogen function)
• Fibrinogen level
• D-dimer
• Mixing study (if aPTT prolonged: does it correct with normal plasma? Yes = deficiency; No = inhibitor)

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High-Yield Summary for Exam Success

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