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Cardiovascular System (CVS) Examination

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1. General Inspection

• Dyspnoea at rest - raised respiratory rate, use of accessory muscles (heart failure)
• Cyanosis - central (lips, tongue) vs. peripheral (fingertips). Central cyanosis indicates right-to-left shunting or severe pulmonary oedema
• Pallor - anaemia, poor perfusion
• Jaundice - right heart failure causing hepatic congestion
• Oedema - peripheral pitting oedema (ankles, sacrum in bed-bound patients) suggests biventricular failure
• Malar flush - butterfly-shaped redness of cheeks seen in mitral stenosis
• Diaphoresis - sweating from sympathetic activation (acute MI, cardiogenic shock)
• Cachexia - chronic heart failure
• Frailty - gait speed, handgrip strength, and muscle wasting should be assessed, particularly in patients undergoing catheter-based interventions

Syndromic Features

Hands and Peripheries

• Clubbing - infective endocarditis, cyanotic congenital heart disease
• Splinter haemorrhages - linear dark streaks under nails, seen in endocarditis (but also trauma)
• Osler's nodes - tender red nodules on finger pulps (endocarditis)
• Janeway lesions - painless erythematous macules on palms/soles (endocarditis)
• Xanthomata - tendon xanthomata (familial hypercholesterolaemia)
• Koilonychia - spoon-shaped nails in iron deficiency (associated with high-output states)
• Capillary refill time - >2 seconds indicates poor perfusion

Eyes and Face

• Corneal arcus - lipid deposition (hyperlipidaemia)
• Xanthelasma - yellowish periorbital plaques (hyperlipidaemia)
• Fundus - hypertensive retinopathy (A/V nipping, flame haemorrhages, papilloedema), Roth spots (endocarditis)

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2. Arterial Pulse

Rate

• Tachycardia: >100 bpm
• Bradycardia: <60 bpm

Rhythm

• Regular
• Irregularly irregular - atrial fibrillation (no two beats the same)
• Regularly irregular - 2nd-degree AV block, bigeminy

Volume (Amplitude)

• High volume: aortic regurgitation, fever, anaemia, thyrotoxicosis, AV fistula
• Low volume: aortic stenosis, cardiogenic shock, pericardial tamponade

Character (Waveform)

Radio-Femoral Delay

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3. Blood Pressure

• Measured in the seated position, arm at heart level, back supported, after 5-10 minutes of rest
• Appropriate cuff size: bladder length 80%, width 40% of arm circumference
• Cuff too small = overestimates; cuff too large = underestimates
• Systolic = first Korotkoff sound; Diastolic = fifth Korotkoff sound (disappearance)
• In severe aortic regurgitation or large AV fistula, diastolic pressure may approach 0 mmHg; record both phase IV and V sounds in these cases
• Check both arms - >15 mmHg difference suggests subclavian stenosis or aortic dissection

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4. Jugular Venous Pulse (JVP)

Measuring JVP Height

• Position patient at 30-45° elevation
• Identify the top of the venous pulsation column
• Measure the vertical distance above the sternal angle (angle of Louis)
• Normal: ≤4.5 cm above the sternal angle
• Venous pulsations visible above the clavicle in the sitting position are always abnormal (distance from clavicle to right atrium is at least 10 cm)
• Elevated JVP predicts pulmonary artery wedge pressure >22 mmHg with a positive predictive value of 88%
• An elevated JVP is an independent predictor of hospitalization and death in heart failure patients

Distinguishing JVP from Carotid Pulse

JVP Waveform Components

Abnormal JVP Patterns

• Large a wave: Pulmonary hypertension, pulmonary stenosis, tricuspid stenosis, reduced RV compliance
• Absent a wave: Atrial fibrillation
• Cannon a waves: Complete heart block, VT, ventricular pacing
• Large v wave: Tricuspid regurgitation (waveform becomes "ventricularized")
• Prominent y descent: Constrictive pericarditis (corresponds to pericardial knock)
• Kussmaul's sign: JVP rises (or fails to fall) with inspiration - indicates constrictive pericarditis or restrictive cardiomyopathy (normally JVP falls with inspiration)
• Abdominojugular reflux (hepatojugular reflux): Sustained JVP rise with firm abdominal pressure for >10-15 seconds - indicates elevated right-sided filling pressures

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5. Inspection of the Precordium

• Apex beat location: Normally at the 5th intercostal space, midclavicular line
• Abnormal pulsations: Visible heaves or pulsations elsewhere are pathological
• Left parasternal heave: RV enlargement or pressure overload
• Right upper parasternal pulsation: Ascending aortic aneurysm
• Epigastric pulsation: May be normal in thin/tall patients or seen in advanced COPD (displaced heart), but also RV hypertrophy

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6. Palpation of the Precordium

Apex Beat

Right Ventricular Palpation

• Left lower sternal border (thenar/hypothenar surface)
• Right 3rd-5th intercostal spaces (finger pads)
• Subxiphoid area
• A parasternal/sternal heave = RV pressure or volume overload
• A zone of retraction between RV and LV impulses may be felt in patients with RV overload when in the left lateral position

Thrills

• Aortic area: aortic stenosis
• Left sternal edge (5th space): VSD
• Apex: mitral regurgitation/stenosis

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7. Cardiac Auscultation

Auscultation Areas

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Heart Sounds

• Caused by mitral and tricuspid valve closure
• Best heard at the apex
• Loud S1: Mitral stenosis (early), hyperkinetic states, short PR interval, tachycardia
• Soft S1: Late mitral stenosis (calcified leaflets), long PR interval, beta-blockers, LV dysfunction
• Variable S1: Complete heart block (changing PR interval), AF
• Normal splitting: appreciated in young patients and RBBB

• Caused by aortic (A2) and pulmonary (P2) valve closure
• Best heard at the base
• Physiological splitting: A2 before P2; widens on inspiration (RV fills more, pulmonary valve closes later), narrows on expiration - normal
• Wide fixed splitting: ASD (right heart volume overload, equal throughout respiratory cycle)
• Wide splitting: RBBB, pulmonary stenosis, RV failure (delayed P2)
• Reversed (paradoxical) splitting: LBBB, severe AS, RV pacing (A2 delayed beyond P2, splits on expiration, narrows on inspiration)
• Loud P2: Pulmonary arterial hypertension
• Single S2: Severe AS (immobile aortic valve), Eisenmenger syndrome

• Low-pitched, early diastole (just after S2) - "Ken-tuc-KY"
• Normal in children, adolescents, young adults
• Pathological in older adults = rapid early ventricular filling in heart failure
• Left-sided S3 = heart failure with reduced OR preserved EF (equally prevalent in both)
• Right-sided S3 = louder at LLSB, increases with inspiration
• A left-sided S3 in chronic heart failure predicts cardiovascular morbidity and mortality

• Low-pitched, late diastole (just before S1) - "TEN-nes-see"
• Indicates presystolic LV expansion due to atrial kick into a non-compliant ventricle
• Seen in LV hypertrophy, active myocardial ischaemia, hypertension
• Absent in atrial fibrillation (no atrial contraction)
• A palpable presystolic impulse corresponding to S4 = marker of reduced LV compliance

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Additional Sounds

• High-pitched, early systole (just after S1), coincides with carotid upstroke
• Bicuspid aortic or pulmonary valve, aortic/pulmonary root dilatation
• Pulmonic ejection sound is the only right-sided sound that decreases with inspiration
• Becomes inaudible as the bicuspid valve calcifies

• High-pitched, early diastole (just after S2), heard at apex/lower sternal border
• The A2-OS interval is inversely proportional to the left atrial-LV pressure gradient
  • Shorter interval = higher gradient = more severe stenosis
• Disappears as leaflets calcify and become rigid

• High-pitched, slightly later than OS, in constrictive pericarditis
• Corresponds to abrupt cessation of ventricular expansion after tricuspid valve opening
• Corresponds to prominent rapid y descent in JVP

• Mitral valve prolapse (MVP)
• Single or multiple non-ejection clicks
• May introduce a late systolic murmur
• Moves toward S1 on standing (decreased preload); moves away from S1 on squatting (increased preload)

• Low-pitched sound, rare, in atrial myxoma
• Diastolic prolapse of the tumor across the mitral valve; may vary with position

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Heart Murmurs

Systolic Murmurs

• MVP: follows mid-systolic click

Diastolic Murmurs (always pathological)

Austin-Flint Murmur

Continuous Murmurs

• Patent ductus arteriosus (PDA): "machinery" murmur, peaks around S2
• Arteriovenous fistula, coronary AV fistula, ruptured sinus of Valsalva aneurysm

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Dynamic Auscultation - Bedside Maneuvers

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8. Peripheral Vascular Examination

Peripheral Pulses

• Level of claudication-producing obstruction can be localized by the level of pulse loss
  • Calf claudication + decreased popliteal pulse = superficial femoral artery obstruction
• Ankle-Brachial Index (ABI): Systolic ankle pressure / systolic brachial pressure
  • Normal: >0.9; Peripheral arterial disease: <0.9; Critical ischaemia: <0.4
• Abnormal pulse oximetry (>2% difference between finger and toe O2 saturation) can detect lower extremity PAD
• Femoral and/or popliteal artery aneurysms should be sought in patients with abdominal aortic aneurysm

Bruits

• A cervical bruit is a weak indicator of degree of stenosis; absence does not exclude significant obstruction
• A bruit extending into diastole or a palpable thrill = severe obstruction
• Also consider an AV fistula with enhanced flow as a cause

Peripheral Signs of Heart Failure

• Pitting oedema: ankles/sacrum; graded 1+ to 4+
• Hepatomegaly: tender, pulsatile in TR; smooth and firm in chronic congestion
• Ascites: advanced right heart failure
• Pleural effusion: typically right-sided or bilateral in heart failure

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Summary Table: Key Exam Findings and Their Diagnoses

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• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Chapter 246: "Cardiovascular Examination," pp. 1904-1910 (McGraw Hill Medical)
• Fuster and Hurst's The Heart, 15th Ed., Chapter 2: "Clinical Cardiovascular Examination" (Miranda & Nishimura)
• Goldman-Cecil Medicine, International Edition: "Physical Examination for Detection of Signs of Cardiovascular Disease"

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Romiplostim (Nplate) - Injection

Overview

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Why Romiplostim Was Developed

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Structure and Chemistry

• Four copies of a small synthetic peptide that binds with high affinity to the TPO receptor (c-MPL)
• Grafted onto an immunoglobulin (IgG1 Fc) scaffold - the antibody portion extends the peptide's half-life in circulation

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Mechanism of Action

1. Proliferation and differentiation of megakaryocyte progenitor cells
2. Maturation of megakaryocytes
3. Production and release of platelets into the circulation

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Pharmacokinetics

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Indications

1. Immune Thrombocytopenia (ITP) - Primary Indication

• Chronic ITP in adults and children who have had an inadequate response to:
  • Corticosteroids
  • Immunoglobulins (IVIG or anti-D)
  • Splenectomy
• Used as second-line or later therapy (in many centres considered alongside splenectomy and rituximab)
• Subcutaneously administered romiplostim (along with oral eltrombopag and avatrombopag) is capable of increasing platelet counts in approximately 70-90% of patients with ITP; some sources cite >90% for durable platelet count improvement

2. Hematopoietic Syndrome of Acute Radiation Syndrome (HS-ARS)

• To increase survival in adults and children (including term neonates) acutely exposed to myelosuppressive doses of radiation

NOT indicated for:

• Thrombocytopenia due to myelodysplastic syndrome (MDS) - see warnings
• Any cause of thrombocytopenia other than chronic ITP (except HS-ARS)
• Normalizing platelet counts in patients where thrombocytopenia is not causing bleeding risk

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Dosing and Administration

ITP (Adults and Pediatrics)

Dose Adjustment Algorithm

Monitoring

• Weekly CBC including platelet count and peripheral blood smear until a stable platelet count is established
• Once stable, monitoring can be reduced to monthly
• Assess peripheral blood smear for cellular morphology (to detect marrow changes)

HS-ARS (Radiation Syndrome)

• Single dose of 10 mcg/kg subcutaneously, administered as soon as possible after confirmed/suspected exposure to myelosuppressive radiation doses

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Preparation and Reconstitution

• Available as a lyophilized powder in single-use vials: 250 mcg/0.5 mL and 500 mcg/1 mL (after reconstitution, concentration = 500 mcg/mL)
• Reconstitute with sterile water for injection
• Administer subcutaneously; injection volumes may be very small (e.g. < 0.1 mL for low-weight patients)
• Single-use only; discard unused portion

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Place in ITP Management

FIRST LINE:
  Corticosteroids (prednisone 1 mg/kg/day or dexamethasone 40 mg × 4 days)
  ± IVIG (1 g/kg × 1-2 doses) for rapid response

SECOND LINE (if relapsed/refractory ~30-40% of patients):
  ├── Thrombopoietin receptor agonists: Romiplostim (SC) / Eltrombopag (oral) / Avatrombopag (oral)
  ├── Rituximab (anti-CD20, ~25% durable remission at 12 months)
  └── Splenectomy (~2/3 durable complete response)

LATER LINE:
  Fostamatinib (SYK inhibitor), immunosuppressants, danazol, etc.

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Adverse Effects and Toxicity

Common

• Injection site reactions - pain, erythema, bruising at injection site
• Headache, fatigue, arthralgia, dizziness, insomnia
• Nausea, abdominal pain, diarrhoea

Important / Serious

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Contraindications / Special Warnings

• MDS: Do not use romiplostim to treat MDS-associated thrombocytopenia - increases risk of AML progression
• Do not use to normalize platelet counts - target is ≥50 × 10⁹/L to prevent bleeding, not normal range
• Avoid concurrent use with another TPO-RA (eltrombopag, avatrombopag, lusutrombopag)
• Chronic liver disease: Use with caution - portal vein thrombosis risk

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Comparison with Other TPO-RAs

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Key Clinical Takeaways

1. Romiplostim does not treat the underlying autoimmune cause of ITP - it compensates for increased platelet destruction by boosting production.
2. Platelet count response begins within 5-7 days; full effect at 10-14 days.
3. It is highly effective (~70-90% response rate) in refractory ITP.
4. The dose is titrated to the platelet count, not the patient's symptoms.
5. Never exceed 10 mcg/kg/week; hold when platelets >400 × 10⁹/L.
6. Monitor for bone marrow fibrosis (peripheral smear changes) with long-term use.
7. Rebound thrombocytopenia can occur after stopping - plan for gradual discontinuation.

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• Katzung's Basic and Clinical Pharmacology, 16th Ed., Chapter 33: "Megakaryocyte Growth Factors," pp. 944-945
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter: "Thrombopoietin Receptor Agonists"
• Goldman-Cecil Medicine, International Edition, Chapter: "Immune Thrombocytopenic Purpura - Second-Line Treatment"
• Washington Manual of Medical Therapeutics, Chapter on Hematology
• Nplate (romiplostim) Prescribing Information, Amgen (current)