INTRACEREBRAL HEMORRHAGE

Risk and prevention of bleeding in anticoagulant therapy

Created 15/04/2021, last revision 20/11/2023

  • anticoagulant therapy is associated with an increased risk of clinically significant bleeding
  • however, antiplatelet therapy is not a safe and effective substitute   AVERROES trial - comparison of apixaban and aspirin
  • specific scales can be used to assess the individual risk of bleeding (see below)
  • always weigh the benefits of therapy against its risks
  • risk of bleeding (mainly intracranial): DOAC < warfarin

Etiopathogenesis of anticoagulation-related bleeding

  • anticoagulants are associated with an increased risk of bleeding, and this bleeding is more likely to be clinically significant
  • several factors can trigger intracerebral bleeding → see here
  • screening for occult bleeding, malformation, or CMBs is not a routine part of the assessment before starting anticoagulant therapy.
  • systemic bleeding most usually occurs in the gastrointestinal or urogenital tract

Risk factors

  • modifiable risk factors

    • blood pressure
    • drug interactions
    • correct anticoagulant dose (e.g., based on weight and/or renal function)
  • mon-modifiable risk factors (cannot be changed)
    • age
    • race/ethnicity
    • comorbidities (renal insufficiency, hepatopathy, etc.)
    • previous ICH  (Schreuder, 2021)

Anticoagulant drug and dose

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Age, race

  • older age is associated with a higher risk of bleeding, but it is not a reason to withhold the therapy
    • dabigatran dose should be reduced at ages ≥ 75-80 (see specifics of each drug)
  • race – higher risk in Asians, Hispanics, and blacks

Recent ischemic stroke

  • in the first days and weeks after a stroke, there is an increased risk of bleeding within the ischemic area (hemorrhagic transformation of ischemia)
  • timing of anticoagulation is guided by the patient’s clinical status (NIHSS), compensation of risk factors (BP, platelets count, coagulation), and CT scan findings (localization and extent of ischemia)

History of bleeding

  • previous bleeding increases risk of recurrence
  • individualized assessment is necessary, but reinstitution of anticoagulant therapy is usually possible and associated with reduced all-cause mortality  [Witt, 2018]
    • risk of GI bleeding can be assessed by endoscopic findings
    • risk of IC bleeding depends on the etiology and modifiable risk factors
    • postoperative bleeding is a transient risk factor

→ timing of anticoagulation after IC hemorrhage

Other comorbidities

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Thrombocytopenia and thrombocytopathy

Thrombocytopenia and coagulation disorders
  • thrombocytopenia with ≥ 50,000 platelets/μL of blood is not a contraindication to AC therapy. For lower counts, assess the cause and individual risk/benefit
  • hemophilia – some types are also associated with a higher risk of thrombosis – hematologist consultation is required
Iatrogenic thrombocytopathy
  • the combination of anticoagulant and antiplatelet drugs increases the risk of bleeding, but is acceptable in certain circumstances
    • after coronary interventions (dual therapy dabigatran + clopidogrel)
    • the benefit of low-dose rivaroxaban 2×2.5 mg + ASA 100mg over ASA alone has been demonstrated (COMPASS trial)
  • do not combine anticoagulants with NSAIDs

Other specific risk factors

Intracranial bleeding
  • intracranial hemorrhage (ICH, SAH) and hemorrhagic transformation of ischemia are the main concerns considering anticoagulant therapy
  • risk factors:
    • previous stroke (mainly ICH due to CAA and hypertensive angiopathy)
    • hypertension – modifiable factor
    • vascular malformation (no evidence of increased risk of rupture on anticoagulant therapy )
    • cerebral microbleeds
    • brain tumor
    • drug abuse (especially cocaine)
    • repeated falls – benefits still outweigh the risk of bleeding
    • endocarditis – septic emboli with bleeding
GI bleeding
  • GI bleeding accounts for ~. 40% of fatal hemorrhages
  • risk factors
    • GI tumor
    • esophageal varices
    • gastritis
    • alcoholism
    • antiplatelet therapy/NSAIDs
    • chemotherapy
  • some experts do not recommend DOACs for the treatment of tumor-associated thrombosis
  • in terms of GI bleeding risk, apixaban and dabigatran seem to be the best choices [Ray, 2018]
  • PPIs should be prescribed in patients with risk factors

Bleeding risk scales

HAS-BLED

→ HAS-BLED score calculator

  • a tool to guide the decision to initiate anticoagulation in patients with Afib
  • always compare the risk for major bleeding (calculated by the HAS-BLED score) with the risk of thromboembolic events (calculated by the CHA2DS2-VASc score) ⇒  does the benefit of anticoagulation outweigh the risk of bleeding?
  • a study comparing HEMORR2HAGES, ATRIA, and HAS-BLED showed superior performance of the HAS-BLED score compared to the other two scores
HAS-BLED score
Hypertension
uncontrolled BP (SBP >160 mmHg)
 1
Abnormal liver/renal function
renal disease – dialysis, transplant, Cr >2.26 mg/dL or >200 µmol/L
liver disease – cirrhosis or bilirubin >2x normal or AST/ALT/AP >3x normal
 1
1
Stroke previous stroke
 1
Bleeding
prior major bleeding or predisposition to bleeding
1
Labile INR unstable INR, time in therapeutic range <60% 1
Elderly age ≥ 65 years
 1
Drugs/alcohol
medication predisposing to bleeding –  aspirin, clopidogrel, NSAIDs
heavy alcohol use
 1
1
HAS-BLED score
Pisters et al. annual ICH risk
Lip et al. annual ICH risk
0 1.1% 0.9%
1 1% 3.4%
2 1.9% 4.1%
3 3.7% 5.8%
4 8.7% 8.9%
5 12.5% 9.1 %
Not enough data for higher scores; risk is most likely > 10%

A score ≥ 3 is associated with an increased risk of major bleeding.
Frequent monitoring, DOAC use, or alternatives to anticoagulation (such as LAA occlusion) are recommended.

ORBIT
  • The ORBIT bleeding risk score has a superior predictive ability for major bleeding in AFib patients compared to the HAS-BLED and ATRIA risk scores. The ORBIT risk score may provide a simple, easy-to-remember tool to assist in clinical decision-making [O´Brian,  2015]  [Hilkens, 2017]
Older age ( >75 y) 1
Reduced hemoglobin/Hct/anemia  (men <13 g/dL and Hct < 40%, women < 12 g/dL and Hct < 36% ) 2
Bleeding 2
Insufficient kidney function (GFR < 60 mL/min/1.73 m2) 1
Treatment with antiplatelets 1
Maximum score 7
score 0–2 – low risk ~ 2.4% / y
score 3 –  medium risk ~ 4.7% / y
score ≥ 4 – high risk ~ 8.1% / y
HEMORR2HAGES
Hepatic/renal disease
 1
Ethanol 1
Malignancy 1
Older age (>75 years) 1
Reduced platelet count or function, including aspirin therapy 1
Re-bleeding risk (history of prior bleed) 2
Hypertension 1
Anemia 1
Genetic factors 1
Excessive fall risk 1
Stroke 1
Maximum points
 12
Bleeding risk per year
Score 0 ~ 1.9 %
Score 1 ~ 2.5 %
Score 2 ~ 5.3 %
Score 3 ~ 8.4 %
Score 4 ~ 10.4 %
Score ≥ 5 ~ 12.3 %

Reduction of bleeding risks

  • correct indication of anticoagulant therapy (regularly check whether the indication is still valid)
  • choose the drug with the best risk-benefit profile (prefer DOACs over VKA if possible)
  • choose the right dose
    • unjustified dose reduction due to fear of bleeding is likely to increase the risk of ischemic stroke  → see Reduced-dose DOACs
  • monitor anticoagulated patients regularly (even those on DOACs!)
  • consider LAA occlusion

Monitoring of anticoagulated patient

In a patient on anticoagulant therapy, check at each visit:

Adherence – check compliance + repeat education

    • switch from warfarin to DOAC (if possible) when INR fluctuates, but good adherence is essential (missing a single dose of DOAC has a greater impact than missing a single dose of warfarin)
    • repeatedly educate the patient on the correct use of the medication
    • advise the patient to carry a medication chart and anticoagulant therapy card in their pocket

Bleeding risk assessment

    • search for bleeding complications
    • review bleeding risk scales –  HAS-BLED score
    • use PPIs if necessary
    • assess the need for dose reduction or drug switching

Creatinine clearance (according to Cockcroft-Gault) – monitor renal function, adjust DOAC dose if needed

    • every 12 months in healthy patients < 75 years of age
    • every 6 months in patients ≥ 75 years of age or frail individuals
    • CrCl/10 is an interval in months in patients with CrCl < 60 mL/min

Drug interaction

    • check for drug interactions – may increase bleeding risk or reduce the anticoagulant effect  (e.g., antirheumatic drugs, verapamil in patients on dabigatran, etc.) → see the chapter on DOACs

Examination and other

    • monitor blood pressure and weight
    • any signs of thromboembolism or bleeding?
    • any adverse reactions?
    • laboratory tests, besides CrCl, may include:
      • blood count, renal and liver tests (at least annually, more frequently in individual cases)
      • specific tests to monitor the anticoagulant effect in selected patients

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Risk and prevention of bleeding in anticoagulant therapy
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