What is the appropriate workup for a patient presenting with random bruising, considering potential underlying bleeding disorders or coagulopathy, and taking into account their medication history and possible anticoagulant use, such as warfarin (coumarin) or aspirin (acetylsalicylic acid)?

Workup for Random Bruising

Begin with a detailed bleeding history using a validated tool, complete blood count with platelet count, PT/aPTT, and fibrinogen level, while carefully assessing medication history for anticoagulants and antiplatelet agents. 1, 2

Initial Clinical Assessment

Bleeding History

• Use the International Society on Thrombosis and Haemostasis bleeding assessment tool to systematically evaluate whether bruising is pathologic 2
• Specifically ask about: spontaneous bruising without trauma, family history of bleeding disorders (particularly maternal inheritance pattern suggesting von Willebrand disease), history of excessive bleeding after circumcision, dental procedures, or surgery, and heavy menstrual bleeding in females 1, 3, 2
• Document location and pattern of bruising—mucocutaneous bleeding suggests platelet dysfunction, while hemarthroses or deep hematomas suggest coagulopathy 2

Medication Review

• Critical priority: Document all anticoagulant use (warfarin, direct oral anticoagulants) and antiplatelet agents (aspirin, P2Y12 inhibitors like clopidogrel) 4, 5
• Review NSAIDs, which inhibit platelet aggregation and can cause gastrointestinal bleeding 5
• Identify medications that interact with warfarin metabolism (amiodarone, propafenone, fibrates, miconazole, phenylbutazone, rifampin, carbamazepine) 6
• Check for corticosteroids, antibiotics (particularly cefazoline), and herbal supplements (garlic, ginkgo biloba, dong quai) that affect coagulation 5, 6

First-Line Laboratory Testing

Essential Initial Tests

• Complete blood count with platelet count: Identifies thrombocytopenia, though normal platelet count does not exclude qualitative platelet defects 1, 2
• Prothrombin time (PT): Detects deficiencies in extrinsic pathway (Factor VII) and common pathway (Factors II, V, X, fibrinogen) 1, 2
• Activated partial thromboplastin time (aPTT): Detects deficiencies in intrinsic pathway (Factors VIII, IX, XI, XII) 1, 2
• Fibrinogen level: Essential because PT/aPTT do not reliably detect fibrinogen defects 4, 1
• Peripheral blood smear: Assess platelet morphology for inherited platelet function disorders 1

Critical Pitfall to Avoid

Normal PT and aPTT do NOT rule out bleeding disorders—these tests miss von Willebrand disease (the most common inherited bleeding disorder with prevalence of 1 in 1,000), Factor XIII deficiency, and platelet function disorders 1, 3, 7

Interpretation Algorithm Based on Initial Results

If PT and aPTT are Normal

• High likelihood of von Willebrand disease or platelet function disorder 1
• Proceed immediately to specialized testing: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and Factor VIII coagulant activity (FVIII:C) 1, 3, 7
• Consider platelet function testing (light transmission aggregometry, PFA-100) if VWD testing is normal but clinical suspicion remains high 4, 1
• Important caveat: Von Willebrand factor is an acute phase reactant and can be falsely elevated during stress or illness, requiring repeated testing for reliable results 3

If PT is Prolonged and aPTT is Normal

• Perform vitamin K challenge (5-10 mg oral or slow IV) 4
• Evaluate for liver disease, vitamin K deficiency, or Factor VII deficiency 1
• In patients on warfarin: Check INR—if INR 5-9 without bleeding, omit 1-2 doses and give vitamin K 1-2.5 mg orally; if INR >9 or active bleeding, give vitamin K 3-10 mg IV with fresh frozen plasma or prothrombin complex concentrate 4

If aPTT is Prolonged and PT is Normal

• Perform mixing study to distinguish factor deficiency from inhibitor 2
• If mixing study corrects: evaluate for Factor VIII, IX, or XI deficiency 1
• If mixing study does not correct: consider lupus anticoagulant or specific factor inhibitor 2

If Both PT and aPTT are Prolonged

• Evaluate for liver disease (check hepatic function panel), disseminated intravascular coagulation (check D-dimer, fibrinogen), or supratherapeutic anticoagulation 4, 1
• In liver disease, viscoelastic testing (TEG or ROTEM) may be more reliable than PT/INR/aPTT for assessing hemostatic function 4

Assessment of Anticoagulant-Related Bruising

For Patients on Warfarin

• If INR is therapeutic (2.0-3.0) and bruising is minor: Reassure patient that local bruising does not adversely affect clinical outcomes 4
• If INR is supratherapeutic (>3.0): Adjust warfarin dose and investigate for drug interactions, dietary changes (vitamin K intake), or acute illness affecting hepatic or renal function 4
• If frequent or excessive bruising occurs at therapeutic INR: Investigate for underlying pathology—anticoagulant-associated bleeding often unmasks occult lesions (25% of patients with gross hematuria on anticoagulants have tumors; 10% with lower GI bleeding have colon cancer) 4
• Consider endoscopy or colonoscopy for GI bleeding, and urologic evaluation for hematuria 4

For Patients on Antiplatelet Agents

• Do not routinely administer platelets for bleeding in patients on aspirin or P2Y12 inhibitors—the PATCH trial showed higher odds of death or dependence with platelet transfusion in ICH patients on antiplatelet therapy 4
• Consider temporarily holding antiplatelet therapy if bruising is excessive and thrombotic risk is acceptable 4

Second-Line Specialized Testing (if first-line testing is normal)

When to Refer to Hematology

• Immediate referral if specialized testing reveals abnormalities requiring interpretation (VWD multimer analysis, platelet function studies, Factor XIII assay) 4, 1, 7
• Refer if bleeding history is convincing but all initial tests are normal—75% of hematologists formally register such patients as having "bleeding disorder of unknown cause" (BDUC) 4
• Refer before surgery if patient has history of excessive surgical bleeding, even with normal screening tests 4

Additional Tests Performed by Hematology

• Platelet function testing (light transmission aggregometry, flow cytometry for platelet surface glycoproteins) 4, 1
• Factor XIII assay (not detected by PT/aPTT) 4, 1
• Thrombin generation assay, thromboelastography (TEG), or rotational thromboelastometry (ROTEM) 4
• Genetic testing for inherited bleeding disorders 4
• Fibrinolysis assays 4

Special Populations

Adolescent Females with Heavy Menstrual Bleeding

• Up to 20% have underlying bleeding disorder, most commonly von Willebrand disease 7
• Quantify menstrual blood loss using Pictorial Bleeding Assessment Chart (PBAC score >100 increases diagnostic sensitivity to 95%) 7
• Immediate specialized VWD and platelet function testing required—do not delay for standard PT/aPTT 7

Elderly Patients

• Consider senile purpura (thinning of blood vessels and skin with aging) as benign cause 1
• Elderly patients require approximately 1 mg/day less warfarin than younger individuals and are more prone to bleeding even at therapeutic INR 4
• Lower threshold for investigating underlying malignancy or vascular lesions 4

Management of Nonmajor Bleeds

• Employ local measures to control bleeding where possible 4
• Temporarily discontinue anticoagulation until clinically stable and hemostasis achieved (decision depends on individual thrombotic risk, nature of bleed, and intensity of anticoagulation) 4
• Do not routinely reverse anticoagulation for nonmajor bleeds 4
• Reassess bleeding risk factors: supratherapeutic anticoagulation, need for invasive procedure, new medications, acute deterioration in renal or hepatic function 4