27.2 Red and White Cell Disorders, Hemoglobinopathies, Factor Deficiencies & Hypercoagulable States
Key Takeaways
Leukostasis is a clinical diagnosis in hyperleukocytosis with respiratory or neurologic symptoms; red cell transfusion raises viscosity and should be deferred until the white count falls.
Hemophilia A with life-threatening bleeding is treated by raising factor VIII activity to 80% to 100%, with each unit per kilogram raising activity by about 2%.
Acquired hemophilia A presents with a prolonged aPTT that fails to correct on mixing study and is treated with bypassing agents plus immunosuppression.
Catastrophic antiphospholipid syndrome involves three or more organ systems within a week and is treated with anticoagulation, corticosteroids, and plasma exchange or IVIG.
Direct antiglobulin testing separates autoimmune hemolysis (warm or cold) from microangiopathic hemolysis, where schistocytes dominate and the test is negative.
Anemia in the Critically Ill
Causes overlap: blood loss (including phlebotomy, which can exceed 40 mL/day), hemodilution, inflammation-driven suppressed erythropoiesis with functional iron restriction, nutritional deficiency, kidney failure, hemolysis, and marrow suppression by drugs or infection.
Work the hemolysis question explicitly:
- Supporting findings: elevated LDH and indirect bilirubin, low haptoglobin, reticulocytosis, and a falling hemoglobin out of proportion to blood loss.
- Direct antiglobulin (Coombs) test: positive in autoimmune hemolysis.
- Warm (IgG): spherocytes; idiopathic, lymphoproliferative disease, lupus, drugs (cephalosporins, penicillins, quinine). Treat with corticosteroids, then rituximab, IVIG, or splenectomy.
- Cold (IgM agglutinin): acrocyanosis and agglutination on the smear; Mycoplasma, EBV, and lymphoma. Keep the patient warm; steroids are less effective, and rituximab or complement inhibition is used.
- Negative antiglobulin test with schistocytes: microangiopathic hemolysis (TTP, hemolytic uremic syndrome, disseminated intravascular coagulation, HELLP, mechanical valve or device hemolysis, malignant hypertension).
- Other patterns: G6PD deficiency with bite cells and Heinz bodies after oxidative stress (rasburicase, dapsone, primaquine, nitrofurantoin, methylene blue, infection); hyperhemolysis after transfusion in sickle cell disease.
- Erythropoiesis-stimulating agents are not recommended for routine ICU anemia; treat iron deficiency when documented.
Polycythemia: distinguish relative (hemoconcentration) from absolute. Polycythemia vera (JAK2 mutation) causes thrombosis, including splanchnic vein thrombosis; treat acute hyperviscosity with phlebotomy and antiplatelet therapy, plus cytoreduction. Secondary polycythemia follows chronic hypoxemia, high-altitude residence, obstructive sleep apnea, or erythropoietin-secreting tumors.
Hemoglobinopathies
- Sickle cell disease crises in the ICU:
- Vaso-occlusive pain crisis: opioids by protocol, hydration (avoid overload), oxygen only for hypoxemia, incentive spirometry to prevent acute chest syndrome, and treatment of triggers.
- Acute chest syndrome (see the pulmonary section).
- Stroke: exchange transfusion plus standard stroke care.
- Splenic sequestration and aplastic crisis (parvovirus B19): transfusion support.
- Priapism, renal papillary necrosis, hepatic crisis, and multiorgan failure also occur.
- Fat embolism from marrow infarction can cause rapid multiorgan failure, treated with exchange transfusion.
- Thalassemia: transfusion dependence with iron overload (cardiac and hepatic), extramedullary hematopoiesis, and infection risk after splenectomy.
- Methemoglobinemia and carboxyhemoglobinemia are covered in the toxicology sections; remember that a "saturation gap" between pulse oximetry and the measured arterial oxygen saturation signals a dyshemoglobinemia.
White Cell Disorders
- Neutropenia: chemotherapy, drugs (clozapine, propylthiouracil, methimazole, sulfasalazine, vancomycin, linezolid), autoimmune disease, and marrow failure. Treat fever immediately (see the neutropenic fever section).
- Hyperleukocytosis and leukostasis:
- A white cell count above about 100,000/µL (lower thresholds matter in acute myeloid leukemia with blasts, which are less deformable than lymphoblasts).
- Leukostasis is a clinical diagnosis: dyspnea and hypoxemia (often with clear radiographs), confusion, visual changes, headache, and priapism.
- Treatment: aggressive hydration, prompt cytoreduction (hydroxyurea or induction chemotherapy), tumor lysis prophylaxis with allopurinol or rasburicase, and leukapheresis for symptomatic leukostasis. Avoid red cell transfusion until the count falls, because it increases viscosity; transfuse platelets freely to reduce hemorrhage risk.
- Acute promyelocytic leukemia is a special case: start all-trans retinoic acid immediately on suspicion because of the coagulopathy, support fibrinogen and platelets aggressively, avoid leukapheresis (which can worsen bleeding), and watch for differentiation syndrome (fever, hypoxemia, infiltrates, weight gain) treated with dexamethasone.
- Hematologic malignancies in the ICU: outcomes have improved substantially, so critical care should not be withheld on diagnosis alone. Watch for tumor lysis, infection with unusual organisms, hyperviscosity in myeloma and Waldenström macroglobulinemia, and spinal cord compression.
- Hemophagocytic lymphohistiocytosis: fever, splenomegaly, cytopenias, very high ferritin, high triglycerides, low fibrinogen, and high soluble CD25; triggered by infection (EBV), malignancy, or autoimmune disease. Treat the trigger with steroids, etoposide, or anakinra; it is frequently mistaken for sepsis.
Factor Deficiencies and Acquired Coagulopathies
| Disorder | Laboratory pattern | Treatment of major bleeding |
|---|---|---|
| Hemophilia A (factor VIII) | Prolonged aPTT, normal PT, corrects on mixing | Factor VIII concentrate to 80% to 100% activity (1 unit/kg raises activity about 2%), then maintenance; emicizumab-treated patients need specialist guidance; desmopressin for mild disease |
| Hemophilia B (factor IX) | Prolonged aPTT | Factor IX concentrate (1 unit/kg raises activity about 1%) |
| Inhibitors in hemophilia | Factor levels fail to rise | Bypassing agents: activated prothrombin complex concentrate (FEIBA) or recombinant factor VIIa |
| Acquired hemophilia A | Prolonged aPTT that does not correct on mixing study; often older adults, postpartum, malignancy, or autoimmune disease | Bypassing agents for bleeding plus immunosuppression (steroids with cyclophosphamide or rituximab) |
| von Willebrand disease | Prolonged aPTT in severe types, abnormal platelet function | Desmopressin (type 1), von Willebrand factor-containing concentrate (types 2 and 3); avoid desmopressin in type 2B |
| Vitamin K deficiency | Prolonged PT first, then aPTT; common in ICU patients on antibiotics with poor intake | Vitamin K 10 mg; 4-factor PCC for major bleeding |
| Liver failure coagulopathy | Global factor deficiency with reduced anticoagulants: rebalanced hemostasis | Do not correct the INR prophylactically; use fibrinogen and targeted products for bleeding |
| Uremic platelet dysfunction | Normal count, abnormal function | Desmopressin, cryoprecipitate, dialysis, conjugated estrogens |
| Factor XIII deficiency | Normal PT and aPTT with delayed bleeding and poor wound healing | Factor XIII concentrate or cryoprecipitate |
Isolated prolonged aPTT in the ICU: consider heparin contamination, lupus anticoagulant (usually thrombotic rather than bleeding), factor deficiency, or an acquired inhibitor. A mixing study separates deficiency (corrects) from inhibitor (does not correct).
Hypercoagulable States
| Disorder | Features |
|---|---|
| Factor V Leiden | Most common inherited thrombophilia in people of European ancestry; activated protein C resistance |
| Prothrombin G20210A | Second most common |
| Protein C, protein S, and antithrombin deficiency | Antithrombin deficiency causes heparin resistance; protein C deficiency predisposes to warfarin-induced skin necrosis when warfarin is started without bridging |
| Antiphospholipid syndrome | Arterial and venous thrombosis, pregnancy loss, thrombocytopenia, prolonged aPTT with a positive lupus anticoagulant, anticardiolipin, or anti-beta-2-glycoprotein I antibody. Use warfarin, not direct oral anticoagulants, especially in triple-positive or arterial disease |
| Malignancy | Trousseau syndrome; use low-molecular-weight heparin or selected direct oral anticoagulants, avoiding the latter with luminal gastrointestinal or genitourinary tumors |
| Heparin-induced thrombocytopenia | See the hematologic emergencies section |
| Paroxysmal nocturnal hemoglobinuria | Hemolysis with thrombosis, including splanchnic and cerebral veins; treat with complement inhibition |
| Nephrotic syndrome, inflammatory bowel disease, hormonal therapy, pregnancy, immobility, and COVID-19 | Acquired risk factors |
Catastrophic antiphospholipid syndrome is defined by involvement of three or more organ systems within a week with histopathologic evidence of small-vessel occlusion and persistent antiphospholipid antibodies. Mortality is high. Treatment combines therapeutic anticoagulation, high-dose corticosteroids, and plasma exchange or IVIG, with rituximab or eculizumab in refractory cases, plus treatment of any trigger such as infection or anticoagulation interruption.
Testing caution in the ICU: acute thrombosis, heparin, warfarin, and acute illness distort thrombophilia assays. Antithrombin, protein C, and protein S are consumed acutely; lupus anticoagulant testing is unreliable on anticoagulants. Defer most thrombophilia testing until the patient has recovered, except where it changes immediate management (such as suspected catastrophic antiphospholipid syndrome or heparin-induced thrombocytopenia).
A 36-year-old man with newly diagnosed acute myeloid leukemia has a white cell count of 180,000/µL with 85% blasts, hemoglobin of 6.8 g/dL, dyspnea, hypoxemia with a clear chest radiograph, and confusion. Which action is most appropriate?
Transfuse 2 units of packed red cells immediately to improve oxygen delivery
Begin hydration and cytoreduction with leukapheresis for symptomatic leukostasis, deferring red cell transfusion
Start dexamethasone alone and reassess in 24 hours
Perform urgent therapeutic plasma exchange with plasma replacement
A 74-year-old woman with no bleeding history develops extensive spontaneous soft tissue hematomas. Her platelet count is normal, PT is normal, and aPTT is 68 seconds. A 1:1 mixing study with normal plasma fails to correct the aPTT, even after incubation. Which diagnosis and treatment are correct?
Hemophilia A, treated with factor VIII concentrate to 80% to 100% activity
Vitamin K deficiency, treated with intravenous vitamin K
Acquired hemophilia A from a factor VIII inhibitor, treated with a bypassing agent plus immunosuppression
Heparin contamination of the sample, requiring a repeat draw only
A 41-year-old woman with known antiphospholipid syndrome stops warfarin before a dental procedure. Four days later she presents with acute kidney injury, livedo reticularis, a new cerebral infarct, pulmonary infiltrates with hypoxemia, and a platelet count of 48,000/µL. Lupus anticoagulant and anti-beta-2-glycoprotein I antibodies remain positive. Which treatment is most appropriate?
Therapeutic anticoagulation plus high-dose corticosteroids and plasma exchange
Platelet transfusion with aspirin monotherapy
Apixaban plus hydroxychloroquine as outpatient therapy
Observation with resumption of warfarin at the prior dose only
Sections you finish are checked off in the contents.