Cerebrovascular pathology and hemopathies

Hematological disorders represent rare causes of strokes (≈ 1% in the general population but 2 to 16% in those under 50 years).

In cases of known hematological disorders, in patients under 50 years, or with certain clinical or biological warning signs, they should be systematically considered (potential specific treatment) during a stroke.

Pathologies of Red Blood Cells: Anemias

Severe acute anemias (++ of hemorrhagic origins, ++ at < 7g/dl) +- severe hypotension → risk of ischemic strokes (++ junctional or distal in the presence of a favoring arterial stenosis).

Chronic anemias (++ of iron deficiency due to occult bleeding) → secondary thrombocytosis and state of hypercoagulability → a favoring factor for ischemic strokes or CVT (case reports).

→ general treatment, correction of anemia and its cause.

Pathologies of Red Blood Cells: Hemoglobinopathies

Sickle Cell Disease

Strokes are reported in 3 to 17% of homozygous sickle cell patients and in 2 to 5% of heterozygous patients. It is one of the etiologies of Moya-Moya syndrome.

Ischemic Strokes

Ischemic strokes in 75% of cases. ++ in childhood among homozygotes, average age of 30 years in heterozygotes.

Very rare: fat embolisms < extensive bone vaso-occlusive crises.

Others

Hemorrhagic strokes (HIP, more rarely isolated SAH) in 25% of cases, ++ 20-30 years. In cases of SAH, an aneurysm is found in 30 to 50% of cases.

Cerebral venous thrombosis is exceptionally reported, generally in cases of associated hemostasis abnormalities.

Management

Acute phase treatment: general measures, hyperhydration, morphine, hematology consultation for exchange transfusions (goal = reduce HbS below 30% without overly aggravating anemia and hyperviscosity).

Chronic treatment to discuss with hematology: long-term exchange transfusions (! risk of hemochromatosis, alloimmunization, infections!), hydroxyurea (Hydrea) or bone marrow transplantation.

In cases of symptomatic Moya-Moya syndrome (high risk of recurrences), surgical revascularization procedures may be considered (weighing risk against hemodynamic repercussions).

Miscellaneous

The involvement of major and intermediate thalassemias has rarely been reported in ischemic strokes. The risk seems increased following blood transfusions and in patients with secondary thrombocytosis due to splenectomy.

Pathologies of Red Blood Cells: Paroxysmal Nocturnal Hemoglobinuria

Recognized etiology of CVT. The usual anticoagulant treatment of CVT is controversial in this case (risk of heparin activating affected platelets).

Controversial etiology of ischemic strokes.

Pathologies of Red Blood Cells: Polycythemias

Ischemic strokes are described in 10 to 20% of patients with essential polycythemia. Significant increase in the risk of CVT. Minor increase in the risk of HIP (severe and advanced polycythemias). Among secondary polycythemias, those related to nephropathies are particularly thrombogenic. In pseudo-polycythemias (++ average age, obese, smokers, hypertension), the role of Hct is debated.

In acute: general measures + consult hematology to consider treatment by phlebotomy/specific treatment.

In chronic: etiological treatment if secondary polycythemia, consider treatment by myelosuppression (repeated phlebotomy increases thrombotic risk), ASA 100mg/day if no major bleeding risk.

Pathologies of Platelets: Thrombocytosis

Ischemic strokes represent 1/3 of the thrombotic manifestations of essential thrombocytosis (++ TIA) and affect 3 to 9% of patients. ++ occlusion of small vessels.

CVT is rare and hemorrhagic strokes are exceptional. No correlation between platelet count and the occurrence of thrombosis. Secondary prophylaxis: antiplatelet therapy, consider chemotherapy.

Discussed responsibility of secondary thrombocytosis (< splenectomy, iron deficiency anemia, etc.).

Pathologies of Platelets: Thrombocytopenia

Bleeding risk, ++ if Pq < 20,000/mm3. Special attention to severe thrombocytopenia induced by heparin.

Pathologies of Platelets: Qualitative Abnormalities

Hypo-platelet activity (on myeloproliferative syndromes, paraproteinemias, iatrogenic causes, etc.) → increased bleeding risk.

Some case reports of ischemic strokes due to hyperaggregability/hyperadhesion of platelets. However, in this case, the diagnosis must be confirmed later: platelet activation markers are often increased secondary to thrombosis.

Pathologies of Platelets: Thrombotic Thrombocytopenic Purpura

The occurrence of willingly recurrent TIAs is common in TTP (fever, nephropathy, thrombocytopenia, microangiopathic hemolytic anemia) (< disseminated hyaline microthrombi). Treatment: plasma exchanges.

Pathologies of Leukocytes: Leukemias

Hemorrhagic strokes frequently occur in all types of leukemias. Due to tumor infiltration, vascular wall lesions, secondary thrombocytopenia (bone marrow infiltration, chemotherapy, DIC), liver failure, infections.

Ischemic strokes and CVT are primarily found in myeloid leukemias, acute lymphoblastic leukemias, and malignant lymphomas. Due to hyperviscosity, leukostasis (due to decreased deformability of white blood cells), subacute coagulopathies from consumption.

Pathologies of Leukocytes: Hyper-Eosinophilic Syndrome

→ increased risk of ischemic strokes < cardioembolic due to underlying heart disease/endomyocardial fibrosis, diffuse vasculopathies, direct neuronal toxicity. Hemorrhages appear to be rarer.

Coagulopathies Associated with Bleeding Risk

Congenital: deficiencies in factor VII linked to X/factor IX, autosomal recessive afibrinogenemias, severe deficiencies in factors VII/X/XI/XIII. → HH strokes at all ages, FF = trauma.

Acquired < liver failure, anticoagulation, fibrinolysis, acute DIC (often associated with malignant hematological disorders, severe sepsis).

Coagulopathies Associated with Thrombotic Risk

Deficiencies in Physiological Coagulation Inhibitors: Antithrombin, Protein C, Protein S

→ Increases the risk of cerebral venous thrombosis (CVT). The risk of arterial ischemic strokes is still debated.

Constitutional deficiencies: autosomal dominant ++++, quantitative or qualitative, demonstrated role of antithrombin deficiency and more moderately of protein C deficiency for CVT. The role of protein S deficiency is debated.

Acquired deficiencies: Debated role – treatment with vitamin K antagonists (VKAs) (proteins C and S) and heparin (antithrombin), severe liver disease, nephrotic syndromes, disseminated intravascular coagulation (DIC), pregnancy (antithrombin and protein S),... acute phase of strokes (activation of coagulation, inflammation or iatrogenic) → levels should be systematically checked afterward.

Abnormalities of Procoagulant Factors

Hyperfibrinogenemia → increases the risk of atheromatous arterial ischemic strokes (++ lacunar) and cardioembolic strokes (due to increased risk of coronary artery diseases).

Resistance to activated protein C (autosomal dominant, in 90% due to mutation in factor V) = the first cause of familial thrombophilia → moderate increase in the risk of arterial ischemic stroke (RR 1.3-1.9) + increased risk of CVT (mutation found in up to 15-20% of CVT cases).

Mutation of the prothrombin gene → moderate increase in the risk of CVT (RR 1.03-1.9, found in 6 to 20% of cases).

Increased activity of factor VIIa and excess of the plasminogen activator inhibitor, factor VIII → risk factor for coronary artery diseases, not demonstrated for strokes. No more evidence-based medicine (EBM) for protein Z. Additionally, should be checked after the acute episode (can increase due to thrombosis).

States of Hypofibrinolysis

Hereditary deficiencies in plasminogen (quantitative/qualitative, constitutional/acquired) → debated increase in the risk of CVT, (arterial ischemic strokes?).

Dys/hypofibrinogenemias = rare, autosomal dominant → recurrent CVT in 10% of patients. Cases of arterial ischemic strokes reported.

Other deficiencies = anecdotal, highly debated.

Subacute and Chronic DIC

Generally encountered < neoplasms (++ adenocarcinomas, papillary ovarian tumors, lymphomas) = secretion of factors activating coagulation, fibrinolysis, and platelet functions. → risk of recurrent multifocal arterial ischemic strokes + risk of cardioembolic strokes from non-bacterial thrombotic endocarditis.

Treatment = etiological. Anticoagulation corrects some biological abnormalities but is not demonstrated to prevent strokes.

Antiphospholipid Antibody Syndrome

Antiphospholipid antibodies are a group of antibodies (e.g., anti-cardiolipin antibodies, circulating anticoagulant). Their presence at certain titres + a thrombotic manifestation (arterial/venous thromboses, recurrent miscarriages) defines an antiphospholipid antibody syndrome.

Primary or secondary syndrome (< systemic lupus erythematosus, ...). Demonstrated cerebrovascular risk in children and young adults. Debated in elderly subjects. Pathophysiology: endothelial dysfunction, platelet activation, inhibition of endogenous anticoagulants, abnormalities in fibrinolysis.

→ risk of ischemic strokes (mode of presentation in 20% of cases) due to in situ thrombosis or cardioembolism (increased risk of thrombi on heart valves) >>>>> risk of CVT.

Treatment: secondary prevention by anticoagulation +- etiological treatment (corticosteroids, immunosuppressants, ...) in case of secondary syndrome.

Paraproteinemias: Multiple Myeloma, Macroglobulinemia

→ Increased risk of hemorrhagic stroke, ++ in cases associated with thrombocytopenia or cryoglobulinemia.

→ Increased risk of ischemic strokes due to hyperviscosity from hyperproteinemia and qualitative abnormalities of paraproteins.

Treatment: possible improvement by plasmapheresis, etiological treatment.

Hemorrheological Factors - Generalities

Main determinants of viscosity: hematocrit, degree of aggregation of red blood cells, deformability of red blood cells, proteins.

Hyperviscosity → decreased blood flow + thrombus formation in capillaries and arterioles.

A contributing factor to stroke in cases of hyperviscosity: arteriolar constriction (++ due to hypoxia).

Etiologies: myeloproliferative syndromes, hemoglobinopathies, dysglobulinemias, inflammation, shock states, burns, gestational toxemia, diabetes, hyperlipoproteinemias, neoplasms, arterial and venous thromboses,...

Bibliography

Bradley WG et al., Neurology in clinical practice, 5th ed., Butterworth-Heinemann, e-dition, 2007

EMC, traité de neurologie, Elsevier, 2018