key: cord-0035038-l592k753 authors: Finke, Jürgen; Bertz, Hartmut; Kaskel, Anna-Katharina; Heinz, Jürgen; Thomas, A.K.; Berger, Dietmar P.; Engelhardt, Rupert; Schmah, Oliver title: Hematology and Hemostasis date: 2008 journal: Concise Manual of Hematology and Oncology DOI: 10.1007/978-3-540-73277-8_6 sha: 5aaef5ab4830bb92870de846135b632476b135eb doc_id: 35038 cord_uid: l592k753 nan Destruction / suppression of hematopoietic stem cells or progenitor cells caused by various factors is of central importance: • Activation of the immune system with primary or secondary (immunologically induced) bone marrow aplasia with activated cytotoxic T-cells, which cause destruction of CD34-positive progenitor cells via: -Direct T-cell-mediated cytotoxicity -Production of IFNγ and TNFβ -Induction of FAS receptor and antigen → apoptosis induction • Direct DNA damage (e.g., irradiation) • Cellular membrane damage and interference with the cellular metabolism (e.g., viral infection) • Drug-induced: direct toxicity or hapten-mediated autoimmune reaction • Secondary clonal expansion of hematopoiesis • NK cells ↓ (as with other autoimmune diseases) • Fanconi's anemia: chromosomal instability based on multiple genetic defects (Fanconi anemia genes FANC A-L). Characteristics are: progressive bone marrow aplasia, increased incidence of malignancy, and abnormalities in skin, musculature, skeletal system, and urogenital system. In > 80% of cases, manifestation is during infancy. • Increased incidence of aplastic anemia in the presence of HLA A2, DR2, DR4, and DPw3. • PNH association (7 Chap. 6.4 • Antibiotics (particularly sulfonamides, chloramphenicol), antimalarial drugs • Thyreostatics, antidiabetics • Antirheumatics, NSAIDs (e.g., phenylbutazone, gold) • Diuretics (furosemide), ticlopidine, nifedipine • Antiepileptics (e.g., carbamazepine, phenytoin) • Cytotoxic compounds (e.g., busulfan) • Aromatic solvents (e.g., benzene) • Insecticides (lindane, DDT, etc.) • Parvovirus B19 (isolated erythropoietic aplasia, "pure red cell anemia") • Hepatitis (non-A-B-C-G hepatitis, poor prognosis, mostly young men) • EBV (infectious mononucleosis, rare) • HIV • Complete blood count: bi-or trilineage cytopenia, generally without pathological morphology, increased granulation, neutropenia, monocytopenia, and eosinopenia; reticulocytes ↓; in cases of thrombocytopenia: small platelets • Ferritin, haptoglobin, Coombs' test, blood group, coagulation parameters • ESR, total protein, electrophoresis, immunoglobulins, immunofixation, cold agglutinins, rheumatoid factor, ANA • PNH exclusion (Ham's test, sugar water test, GPI-linked proteins, CD55, CD59) • Vitamin B12, folic acid (exclusion of megaloblastic anemia) • Liver function (exclude past history of hepatitis) • Serology (EBV, CMV, HAV, HBV, HCV, HIV, HSV, parvovirus B19) • Hypocellular (cellularity < 25%) with predominance of fat cells • Lymphocytes, macrophages, and plasma cells present • CD34-positive progenitor cells ↓; in bone marrow cultures, reduced colony formation (CFU-GM, colony-forming units -granulocytes / macrophages) and LTCIC (long-term culture-initiating cells). Improved growth pattern in T-cell-depleted cultures (→ T-cell-mediated reaction?) • Chest x-ray, abdominal sonography • HLA typing (in cases of potential transplantation) • Cytogenetics, chromosome analysis (exclusion of MDS, Fanconi's anemia) • Increased serum levels of hematopoietic growth factors: G-CSF (granulocyte colony-stimulating factor), TPO (thrombopoietin), M-CSF, and erythropoietin; SCF (stem cell factor) not increased • Myelodysplasia with hypoplastic bone marrow (7 Chap. 7 .2) • Primary Myelofibrosis (PM) (7 Chap. 7.3.4) • Vitamin B12 deficiency, folic acid deficiency (7 Chap. 6.4.2) • Paroxysmal nocturnal hemoglobinuria (PNH) (7 Chap. 6.4 .3) • Leukemias, lymphomas, solid tumors with bone marrow infiltration • Development of PNH in 7% of cases (7 Chap. 6.4 .3) • Transformation into MDS or acute leukemia in 5-12% of cases (7 Chaps. 7.1.1, 7.1.2, 7.2) Indications for Treatment Hematology and Hemostasis • Infection prophylaxis, antibiotics, amphotericin B prophylaxis • Oral hygiene • Prophylaxis / therapy of hemosiderosis (desferrioxamine mesylate) • Granulocyte transfusions (7 Chap. 5.4) • Suppress menses, avoid platelet aggregation inhibitors • Blood products (CMV negative, irradiated); erythrocyte transfusions according to symptoms, platelet transfusions for counts below 5,000-10,000/µl • Growth factors: granulocyte colony-stimulating factor (G-CSF), erythropoietic factors ATTENTION: use blood products as sparingly as possible until decision on BMT / PBSCT is made (danger of alloimmunization). Do not use blood products from relatives. Transplantation Types (7 Chaps. 5.2, 5. 3) • In patients under 55 years of age, allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical related (family) donors in conjunction with fludarabine / cyclophosphamide-containing protocols • Matched unrelated donor (MUD) transplantation recommended only in patients under 15 years of age • Most common form: drug-induced toxic suppression of granulopoiesis or direct neutrophilic damage ("delayed onset neutropenia, " e.g., after radio-or chemotherapy), usually with simultaneous thrombocytopenia (7 Chap. 6 .3) • Drug-induced allergic reactions with destruction of neutrophils, often caused by metabolites • Usually, rapid granulocyte decrease within 1 week after exposure; in case of re-exposure, within hours. Destruction of mature granulocytes ("abrupt onset neutropenia"), acute onset with fever and chills (DD: infection). Causative agent: e.g. phenylbutazone • In rare cases, slow decrease, between 1 and 12 months after the beginning of treatment, due to destruction of hematopoietic progenitor cells. Causative agent: e.g., clozapine, in patients with HLA phenotype B38 and alleles DR4 and DQw3 • Autoimmune diseases: T-cell-mediated inhibition of granulopoiesis (Felty's syndrome, rheumatoid arthritis) or as a result of clonal T-cell expansion in patients with T-γ-lymphoproliferative disease ("T-γ-disease") • Complement activation (e.g., with hemodialysis, sepsis): expression of adhesion molecules on the surface of neutrophils → neutrophilic aggregation, capillary occlusion (esp. pulmonary capillaries) • Pseudoneutropenia ("shift neutropenia"): neutrophilic redistribution (shift) from the peripheral blood into the tissues, e.g., with infections • Congenital dysgenesis with familial pancytopenia • Reticular dysgenesis with congenital aleukocytosis: agranulocytosis + lymphoid hypoplasia + thymic aplasia; unknown etiology • Periodic neutropenia: stem cell regulation defect; neutropenic phases in 10-to 35-day intervals, compensatory monocytosis; autosomal dominant inheritance • Kostmann's syndrome: severe agranulocytosis in children (abnormal differentiation in the promyelocytic stage), reversible by administration of G-CSF (ATTENTION: possibly higher risk of MDS / AML development); autosomal dominant or recessive inheritance • X-linked agammaglobulinemia • Schwachman-Diamond-Oski syndrome: neutropenia + pancreatic insufficiency + metaphyseal dysplasia; unknown etiology; autosomal recessive inheritance • Neutropenia with bi-/ tetraploid leukocytes: abnormal phagocytosis and chemotaxis as well as bi-and tetraploid granulocytes • Chédiak-Higashi syndrome: albinism + neurological disorders + leukocytic granulation abnormalities; unknown etiology • Dyskeratosis congenita: neutropenia, skin abnormalities; X-linked inheritance • Lazy leukocyte syndrome: chemotaxis defect (actin defect); unknown etiology • Cytostatic treatment, immunosuppressives, azidothymidine (AZT), benzenes, ionizing radiation • Idiosyncratic drug reactions (individual sensitivity) in 66% of cases: antibiotics (penicillin, chloramphenicol, cephalosporins, sulfonamides) , sulfasalazine, nonsteroidal antirheumatics (ibuprofen, indomethacin, phenylbutazone), phenothiazine, thyreostatics, quinidine, procainamide, propafenone, ticlopidine, antihistamines, anticonvulsives, nifedipine, levamisole, tamoxifen, allopurinol, tranquilizers, neuroleptics (clozapine), gold, captopril + interferon • Bone marrow aspiration, biopsy and culture (CFU) • Abdominal sonography (spleen), chest x-ray (exclusion of infection) • Leukemia (7 Chaps. 7.1.1, 7.1.2) • Myelodysplasia (7 Chap. 7.2) • Primary Myelofibrosis (7 Chap. 7.3.4) • Aplastic anemia (7 Chap. 6.1) • Susceptibility to infections, fever (7 Chap. 4 .2) • Mucositis, gastroenteritis ("neutropenic enterocolitis") • Hygiene, anti-infectious environment, isolation • Mucositis prophylaxis • Selective intestinal decontamination • Oral antimycosis (e.g., fluconazole 200 mg/day p.o.) • Signs of infection: blood cultures, urine and stool cultures, swabs, immediate start of empirical antibiotic treatment (7 Chap. 4 .2) • With severe infections: granulocyte transfusion (7 Chap. 5.4) • Discontinue all drugs administered within 4 weeks of onset of symptoms • G-CSF (filgrastim, lenograstim) 5-10 µg/kg daily s.c. Treatment according to the assumed pathogenic causes, e.g.: • In patients with clinically relevant recurrent infections, G-CSF may be used as long-term treatment • Use of other hematopoietic growth factors in clinical studies: GM-CSF, IL-3, stem cell factor (SCF) • In cases of autoimmune neutropenia: -Prednisolone 2 mg/kg daily p.o. (maximum 4 weeks) -Cyclosporin A (serum level target: 300-600 ng/ml): initial treatment over at least 4 weeks; if successful, continue for at least 3 months -Azathioprine 2-4 mg/kg daily • With hypersplenism: consider splenectomy (only after pneumococcus vaccination) • In cases of congenital neutropenia: consider allogeneic transplantation (7 Chap. 5 Web: Web: . Neutropenia and Agranulocytosis Decreased platelet count (< 150,000/µl), most common cause of hemorrhagic diatheses. • Thrombopoiesis: megakaryoblasts → megakaryocytes → platelets; regulated by thrombopoietin and other cytokines (e.g., IL-3, IL-6, IL-11) • Directly after being released by the bone marrow, approximately one third of platelets are reversibly stored in the spleen ("pool") • Two thirds of platelets circulate in the blood, life span 7-10 days, biological half-life 3-4 days; 15% of these platelets are spent daily to maintain hemostasis Splenomegaly (portal hypertension, splenic infiltration with hematological neoplasia). • Heart valve and vascular prostheses • Extracorporeal circulation (surface activation) • Immune thrombocytopenia (ITP) (7 Chap. 6.3.1) • Microangiopathic disorders: hemolytic-uremic syndrome (HUS) , thrombotic-thrombocytopenic purpura (TTP) (7 Chap. 6.3 .3) • Disseminated intravascular coagulation (DIC) (7 Chap. 6.5.5) • Disturbances in platelet and coagulation factor interaction: von Willebrand's disease type IIb, heparin-induced thrombocytopenia (HIT) (7 Chap. 6.3 Bone marrow aspiration and biopsy: megakaryocytes ↓ in case of dysfunctional thrombopoiesis, megakaryocytes normal or ↑ in cases of peripheral platelet loss. ATTENTION: if platelet count < 20,000/µl: risk of hemorrhage → iliac crest biopsy (no sternal puncture), apply careful pressure Imaging Chest x-ray (lymphomas, infections), abdominal sonography (lymphomas, spleen) NOTE: if plasmatic coagulation and blood vessels are normal, there is only a low risk of hemorrhage with a platelet count of > 10,000-20,000/µl. "Pseudothrombocytopenia": formation of platelet aggregates in EDTA blood: 0.1-2% of blood samples; cause: autoagglutinating IgG antibodies → In vitro platelet aggregation in the presence of the anticoagulant agent EDTA → False low count by automatic platelet counter → Repeat platelet count with citrated or heparinized blood • Therapeutic: at signs of bleeding or acute hemorrhage (e.g., petechiae, hemorrhage of mucous membranes or epistaxis) with proven thrombocytopenia or thrombocyte dysfunction. • Prophylactic: platelet count < 10,000-20,000/µl. With concomitant diseases (especially acute leukemia, fever, sepsis, splenomegaly) risk of hemorrhage with higher platelet counts (20,000-30,000/µl). With invasive interventions (e.g., catheter installation, punctures) the platelet count target is > 40,000-60,000/µl. To avoid alloimmunization, transfusions should be avoided in patients scheduled for allogeneic hematopoietic stem cell transplantation. Acquired thrombocytopenia, platelet count < 150,000/µl. Classic definition: ITP = idiopathic thrombocytopenic purpura. Diagnosis by exclusion; acquired thrombocytopenia of unknown etiology with normal to increased megakaryocyte count in the bone marrow. Alternative definition: ITP = immune thrombocytopenic purpura. Acquired thrombocytopenia caused by antithrombocytic antibodies. Incidence: 6-10 cases / 100,000 population / year. Distribution male:female = 1:2. IgG-mediated immune reaction (rarely IgM) against platelet membrane antigens, e.g., GPIIb / GPIIIa (fibrinogen receptor), GPIb / IX (von Willebrand receptor), and GPIa / IIa (collagen receptor). • Specific platelet antibodies detectable in approximately 50-70% of cases • Macrophage binding via Fcγ I, II, and III receptors (in ITP patients: receptor polymorphism with altered binding affinity for IgG) • Complement activation • Complement-mediated lysis and enhancement of phagocytosis → RES phagocytosis of IgG-coated platelets, esp. in spleen → Biological half-life of platelets ↓↓ to a few hours • Decreased thrombocytopoiesis (antibodies against megakaryocytes and thrombopoietic progenitor cells) • Possibly T-cell-mediated process (in vitro, CD4 + T-cells can be activated by platelets) • Without known causative disease ("primary ITP") • In conjunction with an underlying disease ("secondary ITP"): lymphoproliferative diseases, autoimmune diseases (systemic lupus erythematosus, etc.), viral diseases (e.g., HCV, HIV), bacterial infections (esp. in children), after bone marrow transplantation • Children: in > 90% of cases, "acute" course: severe thrombocytopenia, usually spontaneous remission within 3 months • Adults: in > 90% of cases, "chronic" course (thrombocytopenia > 6 months): < 5% risk of fatal hemorrhages (esp. intracranial), rarely spontaneous remission (5%), persists for more than 6 months despite adequate treatment in 35% of patients Thrombocytopenia with normal differential and morphology. Normal or reactively increased megakaryocyte count, increased number of immature megakaryocytes. Otherwise, normal bone marrow, no abnormal cells. • Rare with platelet count > 30,000/µl . ITP • Petechial type of hemorrhage (skin, mucous membranes), with hematomas / bruising / epistaxis • Complication: intracerebral hemorrhage (rare), organ bleeding, retinal bleeding, gastrointestinal bleeds The diagnosis of ITP is a diagnosis of exclusion. Therefore, the diagnostic strategies are aimed at identifying potential underlying causes of secondary thrombocytopenia. • Medical history, family history, drug exposure, occupational hazards • Physical examination (petechiae, bruising, mucosal bleeds) • Full blood count with differential • Virology: HCV / HIV serology in patients at risk • Screening for platelet antibodies (50% positive) Bone marrow biopsy and smear in accordance with recommendations of ASH (American Society of Hematology) and BCSH (British Committee for Standards in Hematology): • Patients over 60 years of age • Laboratory abnormalities (neutropenia, anemia) • Prior to splenectomy • Poor response to primary treatment. Differential diagnosis of thrombocytopenia 7 Chap. 6.3 Only a small number of randomized studies have been conducted in ITP. The life expectancy of ITP patients with a platelet count > 30,000/µl is equal to that of the normal population. With higher platelet counts (30,000/µl), treatment is therefore only indicated if blood loss is expected (perioperatively, before delivery) or in the case of active hemorrhage. • Initial response rate > 50%, long-term effect in 30% of patients, low-dose maintenance treatment is required in most cases • Prednisolone 1-2 mg/kg daily, duration of treatment depending on response, or dexamethasone 40 mg/d for 4 days • With durable platelet response: dose reduction of prednisolone over 6-12 weeks, monitoring of platelet counts • If no increment to > 30,000/µl within 2-4 weeks or required steroid dose markedly above the threshold dose for Cushing's disease → change treatment to immunoglobulins or alternative immunosuppressive drugs • Initial response rate 75%, normalization of the platelet count in 50% of patients; however, only transient (up to 4 weeks) • Standard dose: 0.4 g/kg daily i.v. days 1-5 or 1 g/kg daily i.v. day 1 + 2 • Alternative: anti-D IgG in Rh-positive patients, 75 µg/kg body weight over 2-3 days. Disadvantage: i.v. product not available in all countries, high costs In cases of severe or life-threatening hemorrhage: combined administration of methylprednisolone 1 g daily i.v. over 3 days and immunoglobulins 0.4-1 g/kg daily over 2-4 days, platelet transfusion. Due to the short platelet half-life in ITP, the expected platelet need is approximately 2-3 times higher than in other forms of thrombocytopenia. In patients with uncomplicated ITP, platelet transfusions are, generally not indicated. Thrombopoietic agent, binds to TPO receptor and stimulates platelet production of the bone marrow. In Phase III studies in ITP, platelet responses in 80-90% of cases. Starting dose 1 µg/kg once weekly s.c., dose adjustment according to platelet counts. • Immunoapheresis • Rituximab (CD20 antibody) . ITP Acquired heparin-induced thrombocytopenia D69.5 Incidence of HIT type II (see below) with intravenous use of unfractioned heparin (UFH): 2-5%, with use of low-molecular-weight heparin (LMWH): < 0.5%. • Dose-dependent mild early-onset thrombocytopenia (platelet count 100,000-150,000/µl) in the initial 2-3 days of heparin treatment (UFH / LMWH) • Caused by minor heparin-induced platelet aggregation, no immunological genesis • Usually self-limiting (after 1-2 days) while heparin administration is ongoing • Frequency of up to 30% • Dose-independent late-onset thrombocytopenia, 4-20 days after start of heparin treatment (UFH / LMWH). In patients previously exposed to heparin (< 100 days), reoccurrence within hours • Severe thrombocytopenia (platelets < 100,000/µl), median platelet count approximately 60,000/µl, rarely < 20,000/µl or decreased to < 50% of the initial count; worsening of thrombocytopenia if heparin treatment is continued • Thromboembolic complications up to 40 days after heparin administration • IgG antibodies mostly against the platelet factor 4 (PF4)-heparin complex → Immune complex formation → Platelet activation due to binding of the immune complex to the Fc receptor (Fcγ RIIA), PF4 release → Platelet aggregation, endothelial cell damage, thrombin activation → Thromboembolic complications ("white clot syndrome") Clinical relevance: HIT type II: • Main symptom: thrombophilia, not hemorrhage • Warning signs: exanthema or necrosis at injection site • High incidence (up to 53%) of venous and arterial thrombosis, renal dysfunction, pulmonary embolism, infarction (complications may occur weeks after discontinuation of heparin) • Exclusion of other causes of thrombocytopenia (7 Chap. 6 .3). • Combination of a functional test (e.g., heparin-induced platelet activation, HIPA) with ELISA (detection of PF4-heparin complexes). • ATTENTION: if HIT II is clinically suspected, discontinue heparin immediately and use alternatives, even without positive test. The diagnosis of HIT is based on clinical findings. Tests serve as confirmatory tools only. Exclude other causes of thrombocytopenia (7 Chap. 6 .3) Therapeutic intervention (with HIT type II): • Discontinue heparin treatment (UFH / LMWH). ATTENTION: exclude exposure to "hidden" heparin, e.g., coagulation factor products, "heparin lock" of central catheters • Anticoagulation must be continued for at least 4 weeks, using: − Danaparoid sodium: heparin-free heparinoid, ATIII-mediated inhibition of factor Xa, half-life 24 h, renal elimination, monitoring via factor Xa levels, no antidote available − Hirudin derivatives, e.g., lepirudin: bivalent direct thrombin inhibitor, half-life 1.5 h, renal elimination, monitoring via PTT, no antidote available . HIT Thrombocytopenic thrombotic microangiopathies with hemolytic anemia (microangiopathic hemolytic anemia, MAHA). Subtypes: • Thrombotic-thrombocytopenic purpura (TTP, Moschcowitz disease): main symptoms are microangiopathic hemolytic anemia, thrombocytopenia, and neurological symptoms; renal dysfunction in 50% of cases • Hemolytic-uremic syndrome (HUS, Gasser's disease): main symptoms are acute renal failure (renal microangiopathy, glomeruli are particularly affected) and hemolytic anemia; thrombocytopenia and neurological symptoms are less pronounced than in TTP • Toxic microangiopathic hemolytic anemia (toxic MAHA): after treatment with mitomycin C or high-dose chemotherapy It is not yet clear whether TTP and HUS are separate diseases or whether they are different manifestations of one syndrome. Due to the frequently overlapping symptoms, the more commonly used term is TTP-HUS (in adult patients). Exception: HUS in children after E. coli infection. TTP: age peak 30-50 years, distribution male:female = 1:2 HUS: incidence 3-5 cases/100,000 children/year, age peak 1-5 years, distribution male:female = 1:1 • Acquired or congenital (total) dysfunction of the vWF-cleaving protease (= ADAMTS13; a disintegrin and metalloprotease with thrombospondin type-1 motifs; cleaves vWF between the amino acids 842 and 843), with unusually large von Willebrand factor multimers (UL-vWF-M), particularly in chronically recurrent TTP • Acquired TTP: autoimmune disease with anti-vWF protease autoantibodies • Associated with infections (HIV), pregnancy, postpartum, after allogeneic bone marrow transplantation, drugs (mitomycin C, cyclosporine, ticlopidine, clopidogrel, quinine), autoimmune diseases (SLE) • Normal vWF protease activity. • Commonly associated with gastrointestinal infections caused by Shiga toxin or verotoxin-producing Escherichia coli (serotypes OH, particularly O157:H7, O103:HU, O103:H2), rarely shigella (Shigella dysenteriae serotype I). • In the absence of gastrointestinal infections, HUS is probably complement-mediated and occurs in connection with autosomal recessively inherited factor H mutations. In sporadic forms, factor H autoantibodies are thought to be involved. In this case, association with glomerulonephritis type II and involvement of autoantibodies against C3 convertase. Under physiological conditions, vWF multimers are excreted by endothelial cells and deposited subendothelially. In the case of endothelial damage → complex formation of vWF multimers with thrombocytes → thrombocyte aggregation due to binding to platelet glycoproteins Ib, IX, and V as well as activated GP IIb/IIIa. In cases of thrombotic microangiopathies, platelet aggregates or microthrombi are formed in capillaries and small vessels causing infarction, particularly in CNS and kidney. • Thrombocytopenia due to peripheral destruction • Anemia due to mechanical destruction of erythrocytes in partially thrombosed small vessels (fragmentocytes, LDH ↑, haptoglobin ↓↓). . TTP-HUS Thrombotic microangiopathies constitute a hematological emergency → immediate specific treatment is of vital importance. Without adequate treatment, the mortality rate is 90%. • Plasma exchange via pheresis with fresh frozen plasma (FFP) initially 40 ml/kg daily • Aim: depletion of vWF multimers and autoantibodies, substitution of vWF protease (t½ > 24 h) through FFP or as cryoprecipitate • Success parameters: normalization of LDH and platelets, regression of neurological symptoms; once laboratory parameters have normalized, lengthening of pheresis intervals • If symptoms persist: increase pheresis frequency to twice daily or raise volume to 80 ml/kg (in individual cases, as much as 140 ml/kg/day may be indicated → however, twice daily pheresis seems to be more effective); in addition, prednisone (1 mg/kg/day) or methylprednisolone (125 mg i.v. twice daily) and possibly vincristine or immunoglobulins • Pheresis is often accompanied by moderate citrate toxicity (muscle cramps, tetany) → calcium replacement • Even with adequate treatment, full reconstitution of renal function may be delayed • With suspected acquired TTP: prednisolone 3 × 50 mg/day i.v. or p.o. over 1 week, withdraw gradually over a period of at least 4 weeks • Patients with acquired antibody-mediated TTP who respond insufficiently to plasmapheresis or have relapsed: additional immunosuppressive treatment, e.g., splenectomy, immunoadsorption via protein A column, possibly azathioprine or other immunosuppressives (e.g., anti-CD20 antibody rituximab ± cyclophosphamide, cyclosporine). • Congenital vWF protease deficiency: treatment according to symptoms: replacement of vWF protease ± plasmapheresis, prophylactic platelet aggregation inhibitors may be required with platelet recovery. Platelet transfusion only after careful benefit-risk assessment (e.g., life-threatening hemorrhage) → possible deterioration of symptoms (increased intravascular thrombus formation). . TTP-HUS Reduced hemoglobin concentration and hematocrit. Red blood cell (RBC) number below normal level. Substitution of packed red blood cells: restrictive indication (7 Chap. 4.9.1). • Individual assessment of transfusion indication for each patient. • In acute blood loss, consider indication when hemoglobin < 8.0 g/dl. • With chronic anemia lower levels of hemoglobin (6-8 g/dl) are generally tolerated. • Patients with coronary heart disease or risk of cerebral ischemia: transfusion indication at hemoglobin < 10 g/dl. • Specific conditions (surgery, thalassemia major, etc.) may require RBC transfusion support. The indication for transfusion is based on clinical symptoms. Asymptomatic blood loss does not constitute an indication for transfusion. Anemias with decreased corpuscular hemoglobin (MCH < 28 pg) and decreased corpuscular hemoglobin concentration (MCHC < 32%): • Iron deficiency anemia (> 90% of hypochromic anemias) • Anemia of chronic disease (inflammation-/ infection-/ tumor anemia) • Thalassemia (7 Chap. 6.4 .3) • Rare causes: vitamin B6 deficiency, lead intoxication Iron deficiency anemia Most frequent form of anemia. Proportion male:female = 1:5. About 10-20% of women in childbearing age demonstrate latent iron deficiency. Daily iron resorption required: men 1 mg, women and adolescents 2-3 mg, pregnant women 3-4 mg. About 60-70% of body iron store bound in hemoglobin, additional 10% in myoglobin. 1 g hemoglobin contains 3.4 mg of iron. In iron deficiency the iron need is greater than the available iron supply, resulting in hemoglobin synthesis disorders → microcytic, hypochromic erythrocytes. • Ferritin serum : correlates with total iron (↓ in iron deficiency) • Transferrin serum : correlates with circulating iron and need (↑ in iron deficiency) Most important cause: loss of iron due to chronic bleeding → in manifest iron deficiency evaluation of underlying cause is of central importance. Microcytic, hypochromic erythrocytes, poikilocytosis, anisocytosis, anulocytes. Iron stain (Prussian blue stain): storage iron not detectable (ferritin, hemosiderin). • Skin and nail changes: skin atrophy, spoon-shaped nails (koilonychia) • Oral rhagades, impairment of mucous membranes, in extreme cases painful mucous membrane atrophy of tongue, pharynx, and esophagus with dysphagia (Plummer-Vinson syndrome) • History, esp. infections, drugs, bleeding, nutritional habits • Physical examination: including skin, mucous membranes, lymph node status, spleen / liver, heart (tachycardia, particularly systolic murmur), rectal examination with fecal blood test, urine dipstick • Gynecological examination • Endoscopy: esophago-gastro-duodenoscopy, colonoscopy, rectoscopy • Hematology: blood count, MCV ↓, MCH ↓, reticulocytes, differential blood count • Clinical chemistry: routine tests with bilirubin, renal function parameters, iron status (iron ↓, ferritin ↓, transferrin-binding capacity ↑) • Blood group (if red cell substitution necessary) • Iron resorption test (if resorption deficiency is suspected) In inconclusive cases eventually bone marrow aspiration / biopsy, including iron staining, to exclude other causes of anemia. • Anemia of chronic disease (iron ↓, ferritin normal or elevated, transferrin-binding capacity ↓) • Thalassemia (MCV ↓↓, iron, ferritin, and transferrin-binding capacity normal) • Hemolytic anemia (bilirubin, LDH, haptoglobin, Coombs' test) Treatment of anemia with iron deficiency always requires a combined approach: 1. Treatment of the underlying cause of iron deficiency (e.g., chronic blood loss) 2. Iron substitution • Application of ferrous II preparation, e.g., Fe(II) sulfate, fumarate, gluconate, or succinate, 100-200 mg/day p.o., for 2-6 months. • PKIN: oral bioavailability, depending on preparation, 15-25%, better bioavailability when taken prior to food. • SE: gastrointestinal tract symptoms (nausea, vomiting,), dark discoloration of stool (ATTEN-TION misdiagnosis: upper gastrointestinal bleeding). • Treatment monitoring: after 5-7 days reticulocytes ↑, hemoglobin ↑. Most frequent cause of a treatment failure is lack of compliance, followed by combined anemia (e.g., coexisting iron deficiency and lack of vitamin B12). • Parenteral application of iron should be limited to individual cases (e.g., in malabsorption syndrome), due to severity of side effects. • Strictly intravenous application of ferrous(III) preparations, consider premedication with steroids and antihistaminics. • SE: thrombophlebitis, headache, flush, nausea, vomiting, fever, allergic reactions up to anaphylaxis. With paravenous injection local pain and visible iron deposits in tissue. Application of packed red blood cells is generally not indicated in iron deficiency anemia. Exceptions exist in patients with additional blood loss and clinical symptoms. Second most common form of anemia (after iron deficiency anemia). Multifactorial anemia with chronic underlying disease (malignancy, inflammation, infection, collagen diseases). Pathogenetic factors: • Cytokine-mediated (TNFα, interleukin-1, interferon γ) → erythrocyte-survival time ↓, interference with iron mobilization from reticuloendothelial iron stores (macrophages), iron uptake / utilization in normoblasts ↓, erythropoietin secretion and effect ↓, inhibition of erythroid progenitor cells, etc. • Treatment-associated (drugs, radiation therapy, etc.) • Consequence of underlying disease Normochromic, normocytic or hypochromic, microcytic red blood cells, poikilocytosis, anisocytosis. • Pallor of skin and mucous membranes, nail beds, conjunctivae • Weakness, tiredness, reduced performance, exertional dyspnea • Lack of concentration, headache Depending on disease, generally with • Tiredness, weakness, reduced performance • Fever, weight loss, night sweats (B symptoms) • Loss of appetite, myalgia, arthralgia, etc. In inconclusive cases consider bone marrow aspiration / biopsy, including iron staining, to exclude other causes of anemia. Anemia with increased erythrocyte volume (MCV > 98 fl), usually caused by lack of vitamin B12 (cobalamin) and/or folic acid. Incidence 5-10 cases/100,000 population/year, distribution male:female = 3:2, age peak 60 years The reference nutrient intake (RNI) for vitamin B12 is 1 µg, with maximum daily absorption in the terminal ileum of 2-3 µg. "Intrinsic factor" (glycoprotein) is a prerequisite for vitamin B12 resorption. • Cofactor in the synthesis of succinyl CoA, methionine, and tetrahydrofolic acid • In case of vitamin B12 deficiency: → DNA synthesis and fatty acid metabolism impaired → Delayed nuclear maturation, normal cytoplasmic development → Ineffective myelopoiesis, large cells with altered nucleus: plasma ratio • Most frequent cause: pernicious anemia (80% of cases): autoimmune atrophic gastritis with antibodies against gastric parietal cells (90% of cases) and/or antibodies against intrinsic factor (50% of cases) → Achlorhydria, intrinsic factor deficiency → Decreased vitamin B12 resorption in the terminal ileum • Insufficient vitamin B12 uptake (strict vegetarians, alcoholics) • Postoperatively (gastrectomy, resection of the terminal ileum, blind loop syndrome) • Vitamin B12 malabsorption, rare (Crohn's disease, scleroderma, amyloidosis) • Infections / parasites (fish tapeworm, bacterial gastrointestinal infections) Macrocytic hyperchromic erythrocytes, poikilocytosis, anisocytosis, hypersegmented granulocytes (right shift); in severe cases, granulocytopenia and thrombocytopenia. Megaloblastic changes: ineffective left-shifted erythro-, thrombo-, and granulopoiesis, pronounced erythropoiesis with increased numbers of immature erythroid precursors (erythropoietic hyperplasia with megaloblastic erythroblasts), giant band forms, immature megakaryocytes. • Pale skin and mucous membranes, icterus (due to intramedullary hemolysis) • Weakness, fatigue, reduced performance, dyspnea on exertion • Difficulty concentrating, headache In advanced cases: funicular myelosis: neuropathy caused by symmetrical damage of the posterior columns of the spinal cord, the corticospinal tract and peripheral nerves; motor abnormalities mainly affecting the lower extremities; staggering gait, ataxia, spastic paresis, impaired vision, psychological disorders. • Type A gastritis • Trophic disorders of the skin and mucous membranes: Hunter's glossitis, etc. • Sterility (gonad dysfunction), reversible • Medical history: infections, drugs, hemorrhage, nutritional habits • Physical examination: skin, mucous membranes, lymph node status, spleen / liver, heart (tachycardia, in some cases: systolic cardiac murmur), rectal examination and test for fecal blood, neurological examination • Hematology: blood count with MCV (↑), MCH (↑), reticulocytes (↓), differential blood count • Clinical chemistry: liver and renal function tests, total protein, hemolysis parameters (bilirubin ↑, LDH ↑↑, haptoglobin ↓ due to intramedullary hemolysis) • Antibodies against gastric parietal cells and/or against intrinsic factor • Vitamin B12 serum level (normal: 200-900 pg/ml), folic acid serum level • Vitamin B12 absorption test (Schilling's test): oral administration of radioactive B12 ± intrinsic factor, determination of urinary vitamin B12, comparison of vitamin B12 absorption / excretion with and without intrinsic factor • Blood group (if red cell transfusion is necessary) • Gastroscopy: detection of chronic atrophic gastritis, exclusion of gastric carcinoma (incidence 3 times higher with chronic atrophic gastritis) • Bone marrow aspiration / biopsy to confirm megaloblastic abnormalities • Alcoholism (most common cause of a macrocytic blood count) • Hepatic disorders, severe hypothyroidism • Reticulocytosis, myelodysplasia (7 Chap. 7 Hydroxycobalamin 1 mg i.m. → initially: 6 injections within 2-3 weeks (to replenish vitamin B12 stores), then: one injection every 3 months. Additionally: application of ferrous II preparation and folic acid to cover increased erythropoesis during substitution phase. ATTENTION: close monitoring during the first days of treatment: critical increase in reticulocytes and platelets possible → increased risk of thrombosis, potassium and iron deficiency. Gastroscopy at regular intervals due to increased risk of gastric cancer. Reference nutrient intake (RNI) for folic acid: 100-200 µg, during pregnancy 400 µg. • Folic acid is a cofactor of thymidylate synthesis (C1 transfer), i.e., DNA synthesis • In case of folic acid deficiency: → Disorder of DNA synthesis → Delayed nuclear maturation with normal cytoplasmic development → Ineffective myelopoiesis, giant cells with an abnormal nucleus: plasma ratio • Insufficient folic acid intake: nutritional deficiency, alcoholism, anorexia nervosa • Malabsorption: gluten-induced enteropathy, tropical sprue, Crohn's disease, scleroderma, amyloidosis, postoperatively (small bowel resection, gastrectomy) • Increased demand: pregnancy, chronic hemolytic anemia, chronic inflammatory disease, or malignancies • Loss of folic acid: hemodialysis • Drug-induced (with folic acid antagonists): methotrexate, trimethoprim, pyrimethamine, phenytoin, triamterene See Vitamin B12 Deficiency Anemia • Pale skin and mucous membranes, icterus (due to intramedullary hemolysis) • Weakness, fatigue, reduced performance, dyspnea on exertion • Difficulty concentrating, headache • Folic acid deficiency during pregnancy: increased incidence of neural tube defects (spina bifida, anencephaly) • Sterility (gonadal dysfunction), reversible • Hematology: blood count with MCV (↑), MCH (↑), reticulocytes (↓), differential blood count • Clinical chemistry: liver and renal function tests, total protein, hemolysis parameters (bilirubin ↑, LDH ↑, haptoglobin ↓ due to intramedullary hemolysis) • Vitamin B12 level, folic acid level (normal: 6-20 ng/ml) • Blood group (if red cell transfusion is necessary) • Esophago-gastro-duodenoscopy: exclusion of gluten-sensitive enteropathy (sprue) • Bone marrow aspiration / biopsy to confirm megaloblastic abnormalities See Vitamin B12 Deficiency Anemia Anemia caused by erythrocyte destruction characterized by decreased erythrocyte survival (< 120 days) In the bone marrow, 2 × 1011 erythrocytes are produced per day; median erythrocyte survival: 120 days; erythrocyte destruction in spleen and liver (reticuloendothelial system, RES). Generally, normochromic normocytic anemia with normal leukocytes and platelets; characteristic changes in cases of hereditary membrane defects (spherocytes, elliptocytes, etc.); anisocytosis, poikilocytosis, and, in some cases, fragmentocytes. . Hemolytic Anemia Erythropoietic hyperplasia, increase in erythroblasts. Consider bone marrow aspiration / biopsy, including iron stain, to exclude other causes of anemia. Therapeutic options depend on the anemia subtype. Treatment components are: • Supportive treatment: red cell transfusion (only in individual cases with symptomatic anemia, controversial in cases of autoimmune hemolytic anemia) • Treatment of underlying disease • Immunosuppression (in cases of autoimmune hemolytic anemia) • Splenectomy → removal of the sequestration filter for damaged erythrocytes ATTENTION Splenectomy • Splenectomy can correct the decrease in erythrocyte survival, but it is not a causal therapy in the sense of a correction of the triggering hemolytic defect. • Prior to splenectomy, MANDATORY vaccination against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae because of the sepsis risk. • After splenectomy, prevention of thromboembolic events (platelets ↑) → low-dose heparin. Most common hereditary hemolytic disease; prevalence 0.02%; in most cases hereditary disease (autosomal dominant), spontaneous mutation is rare. Rare, higher incidence in Mediterranean countries / Africa (increased malaria resistance of elliptocytes) Heterogenic disease group with > 25% of elliptic erythrocytes; protein defects of the erythrocytic cytoskeleton (spectrin, protein 4.1R) Usually asymptomatic; only 10-30% of patients have varying degrees of anemia, icterus or hemolytic crises • Positive family history • Blood smear with > 25% elliptocytes In symptomatic patients: splenectomy Acquired clonal disorder of myeloid stem cells (i.e., of the erythrocytic, granulocytic, and thrombocytic line) with somatic mutations of phosphatidylinositol-glycan A (PIG A) → defect of the "phosphatidylinositol-glycan anchor" (PIG anchor) The PIG anchor fixes various proteins to the cell membrane, including three complement-regulating proteins: CD59 (membrane inhibitor of reactive lysis; MIRL), CD55 (decay accelerating factor; DAF), and "C8 binding protein" (CBP). → Changes in the PIG anchor lead to a decrease in the respective proteins in the cell membrane → Reduced resistance against activated complement factors → Complement-mediated lysis ↑, incidence of thromboembolic events ↑ • Chronic hemolytic anemia • Different severity levels of nocturnal hemolysis (even nocturnal hemolytic crises), with morning hemoglobinuria • Recurrent thrombosis, particularly portal vein, liver veins (Budd-Chiari syndrome), cerebral vessels, splenic vein, skin veins (skin necrosis) • Iron deficiency anemia due to chronic loss of iron (renal) • Medical history: circadian occurrence of symptoms • Physical examination: anemia signs and symptoms, urinary discoloration • Normochromic normocytic anemia, in some cases with granulocytopenia and thrombocytopenia • Hemolysis parameters (LDH ↑, haptoglobin ↓, indirect bilirubin ↑, hemoglobinuria) • Acid hemolysis test (Ham's test) and sugar water test (sucrose test), pathological: complementmediated lysis after addition of sugar water or acid to the blood sample • Molecular genetic proof of the PIG defect In rare cases development of aplastic anemia, myelodysplasia, or AML • Prophylactic anticoagulant therapy: phenprocoumon. ATTENTION: avoid heparin → possible complement activation • Iron and folic acid supplementation • In cases of hemolytic crisis: corticosteroids (prednisolone 50-100 mg i.v.), supportive treatment • Blood transfusion: only washed erythrocytes to avoid administration of additional complement • Eculizumab, antibody against complement c5, inhibits complement-mediated lysis of PNH erythrocytes Allogeneic stem cell transplantation (7 Chap. 5. 3): only in severe cases with repeated hemolytic crises or complications (thromboembolic events, etc.) Hereditary disease, genetic modification of the glucose-6-phosphate dehydrogenase (> 300 mutants worldwide) One of the most common hereditary diseases worldwide, regional differences in incidence and prevalence. In Africa, Asia, and the Mediterranean region, as much as 20-60% of the population may be affected (patients are more resistant to malaria plasmodia). X-chromosomal recessive inheritance → mainly males affected. Heterozygotics have two different populations of erythrocytes and usually have less pronounced symptoms. Hereditary defect of the enzyme pyruvate kinase, i.e., the erythrocytic glycolysis. Most common hereditary glycolytic defect (Embden-Meyerhof pathway), autosomal recessive inheritance. Heterozygotic individuals are usually asymptomatic. Homozygosis (rare) leads to hemolytic anemia. Pyruvate kinase deficiency results in abnormal glycolysis: → ATP deficiency → abnormal Na + / K + -ATPase activity in the erythrocyte membrane → Membrane instability, hemolysis Usually asymptomatic. In homozygotic individuals, hemolytic crises may occur. • Blood smear with acanthocytes, anisocytosis, poikilocytosis • Hemolysis parameters, reduced erythrocytic pyruvate kinase activity Symptomatic patients: splenectomy; in cases of iron overload: venesection therapy and administration of desferrioxamine. Hemoglobin S (HBS): point mutation in the β-globin locus (chromosome 11) of the hemoglobin molecule in position 6: replacement of glutamic acid by valine (β6 Glu → Val). HBS precipitates when deoxygenated (risk factors: lack of oxygen, dehydration, fever, increased serum osmolality, stasis): → Sickle-shaped erythrocytes with reduced elasticity → Hemolysis, disturbed microcirculation, capillary occlusion Heterozygotic individuals (HBAS) are usually asymptomatic. In homozygotic cases (HBSS): • Hemolytic anemia and hemolytic crisis • Vaso-occlusive crises: organ infarction (particularly spleen, kidney, CNS), bone infarction, pulmonary hypertension • Abdominal pain, bone pain, cerebral disorders, in some cases with fever, tachycardia, leucocytosis • Hepatosplenomegaly, recurrent splenic infarction → "autosplenectomy, " functional asplenia • Osteoporosis, growth defects due to recurrent bone infarction • Pure red cell aplasia / aplastic crisis with parvovirus B19 infections • Proliferative retinopathy → impaired vision • Bilirubin gall stones • Immunodeficiency (due to recurrent splenic infarction) • Medical history (family history), clinical examination • Hemoglobin electrophoresis • Sickle cell test: erythrocytes show sickle shape after addition of sodium sulfide • Molecular genetic screening (PCR) Other hemoglobinopathies: more than 450 hemoglobinopathies have been described. HB C, E, and D are the most common. Sickle cell anemia is treated supportively: • Fluid replacement, at least 2,000 ml/day • Oxygen (via nasal tube, 3-4 l/min) • Treatment of infections, analgesia • Red cell transfusion, in case of severe complications: exchange transfusion • In cases of splenic infarction / hemorrhage / rupture: splenectomy • Prophylactic pneumococcus vaccination • Hydroxyurea Prevention of lack of oxygen, dehydration, and infections. Quantitative disturbance of hemoglobin synthesis due to a genetic defect in globin chain formation. Subtypes: • β-Thalassemia: abnormal β-chain synthesis • α-Thalassemia: abnormal α-chain synthesis (rare) Regional differences in incidence: β-thalassemia in Mediterranean regions, Africa, and Asia; αthalassemia in South East Asia and Africa. Abnormal synthesis of the hemoglobin β-chain, i.e., no formation of normal adult HBA1 (αα/ββ). → Compensatory formation of γ-or δ-chains (HBF = αα/γγ and HBA2 = αα/δδ) → Ineffective erythropoiesis (free α-globin is toxic for erythroblasts) with intramedullary hemolysis → Hypochromic microcytic anemia, signs of hemolysis . Hemolytic Anemia Hematology and Hemostasis Usually, no clinical symptoms; in some cases minor chronic hemolysis, anemia, and splenomegaly. • Chronic hemolysis, icterus • Hepatosplenomegaly • Cardiac insufficiency • Infections • Microcytic hypochromic anemia (HB ↓, HCT ↓, MCV ↓, MCH ↓) • Iron serum ↑, ferritin ↑, transferrin iron-binding capacity ↓ • Blood smear: microcytic hypochromic erythrocytes, target cells, polychromasia, isolated normoblasts • Chronic erythropoietic bone marrow hyperplasia → expanded marrow, detectable in bone marrow scan or skull x-ray ("hair-on-end" sign) • Hemoglobin electrophoresis: increase in HBF (αα/γγ) and HBA2 (αα/δδ) • Molecular genetic detection of the defective globin gene (via PCR) Iron deficiency anemia (7 Chap. 6.4.1) . • RBC transfusion • Hemosiderosis treatment: desferrioxamine 2,000 IU/day s.c. In homozygotic cases / severe hemolysis: allogeneic stem cell transplantation during infancy. Autoimmune hemolytic anemia caused by IgG incomplete "warm" autoantibodies (incomplete antibodies: antigen-antibody binding, but no lysis or agglutination). Seventy-five percent of all autoimmune hemolytic anemias. • In non-Hodgkin's lymphoma, particularly in low-malignant NHL (CLL) • With autoimmune diseases, e.g., systemic lupus erythematosus (SLE) • Following infections (viral infections, rarely bacterial infections) • Drug-induced hemolysis (various mechanisms): antibiotics, α-methyldopa, L-dopa, quinine, quinidine, x-ray contrast agents, procainamide, diclofenac • Idiopathic (50% of cases) • Binding of incomplete antibodies to erythrocytes • Destruction of antibody-coated erythrocytes in spleen and liver (extravascular non-complement-mediated lysis by cells of the reticuloendothelial system) • Hemolysis and hemolytic crises, with icterus, hemoglobinuria, fever, etc. • Anemia symptoms (fatigue, weakness, reduced performance, pallor, headache, etc.) • Case history including medication • Physical examination including signs and symptoms of anemia Treatment of underlying disease or discontinuation of causative drugs. • Corticosteroids (prednisolone 100-500 mg/day i.v.), slowly taper dose after hemolysis parameters have normalized • In cases of chronic hemolysis and poor response to corticosteroids: use alternative immunosuppressive agents, e.g., azathioprine 80 mg/m2/day, cyclophosphamide 60 mg/m2/day p.o. • Splenectomy: in cases of treatment-refractory chronic hemolysis or refractory acute hemolytic crisis • Transfusion of packed red cells only in cases of symptomatic anemia (e.g., cardiovascular symptoms, dyspnea, cerebral ischemia) Autoimmune hemolytic anemia caused by IgM complete "cold" autoantibodies, usually targeting the I-antigen of the erythrocyte membrane (complete antibodies: capable of agglutination and lysis induction after antigen-antibody binding). Fifteen percent of all autoimmune hemolytic anemias. • In low-malignant non-Hodgkin's lymphoma or Hodgkin's disease • After infection (viral infections, mononucleosis / EBV infection, mycoplasma pneumoniae) → cold agglutinin titer up to 1:1,000 Rare congenital disease → Cold agglutinin titer up to 1:256,000 When the intravascular temperature drops to < 20-25°C: antigen-antibody binding, agglutination and complement-mediated intravascular hemolysis. • Exposure to cold leads to hemolysis and hemolytic crisis (with icterus, hemoglobinuria, fever, etc.) • Anemia symptoms (fatigue, weakness, reduced performance, pallor, headache, etc.) • Acrocyanosis: painful / malperfused extremities (fingers / toes / nose) • Splenomegaly . Hemolytic Anemia Hematology and Hemostasis • Medical history, physical examination • Diagnostic clues: erythrocyte agglutination when blood is drawn and during laboratory analysis • Anemia (HB ↓, HCT ↓), signs of hemolysis (LDH ↑, indirect bilirubin ↑, haptoglobin ↓), detection of cold autoantibodies • Exclusion of potential underlying diseases • Blood group Treatment of the underlying disease. • Protection against cold • With severe acute hemolysis: plasmapheresis (objective: removal of autoantibodies), often technically difficult (due to agglutination within the plasmapheresis system) • With chronic hemolysis: immunosuppressive drugs, e.g., azathioprine, cyclophosphamide, or chlorambucil • With symptomatic anemia (cardiovascular symptoms, dyspnea, cerebral malperfusion, etc.): transfusion of washed packed red cells (avoid complement administration in cases of complement-mediated hemolysis) • Corticosteroids and splenectomy are usually ineffective Anemia with normal corpuscular hemoglobin (MCH 27-34 pg) and normal corpuscular hemoglobin concentration (MCHC 31-36 g/dl). • Hemolytic anemia (7 Chap. 6.4 .3) • Aplastic anemia (7 Chap. 6.1) • Acute posthemorrhagic anemia • Renal anemia Normochromic normocytic hyporegenerative anemia as a result of chronic renal failure. Incidence: 50-60 cases/100,000 per year. • Complex pathogenesis based on renal insufficiency • Renal erythropoietin synthesis ↓, the degree of anemia correlates with the severity of the underlying disease • Myelosuppresion and intramedullary hemolysis due to accumulation of uremic toxins • Concurrent chronic blood loss due to hemodialysis • Pale skin and mucous membranes • Weakness, fatigue, reduced performance, dyspnea on exertion • Difficulty concentrating, headache • Uremic fetor • "Café au lait" complexion due to urochrome deposits and concurrent anemia, pruritus • Weakness, headache • Medical history: signs of chronic renal insufficiency • Physical examination: skin, mucous membranes, lymph node status, spleen / liver, heart (tachycardia, systolic heart murmur), rectal examination and testing for fecal occult blood • Hematology: blood count including MCV (normal), MCH (normal), reticulocytes (↓), differential blood count • Clinical chemistry: hepatic and renal function tests, total protein, hemolysis parameters (bilirubin, LDH, normal haptoglobin, low-grade hemolysis due to uremic toxins) • Vitamin B12 level, folic acid level • Serum iron, ferritin, transferrin; in cases of chronic blood loss due to hemodialysis, iron deficiency may occur • Erythropoietin ↓ / normal (i.e., inadequate increase given the degree of anemia) • Blood group (if red cell transfusion is required) • Erythropoiesis stimulation with darbepoetin 1.35 µg/kg body weight once weekly s.c. or i.v., adjust dose according to hemoglobin response • Alternatively, recombinant erythropoietin, 50 IU/kg body weight three times weekly s.c. or i.v., adjust dose according to hemoglobin response . Normochromic Anemia • Target hemoglobin 10-12 g/dl • ATTENTION: blood pressure may rise as hematocrit increases, especially in cases of pre-existing hypertension • Hemodialysis • Additional iron supplementation with signs of iron deficiency (7 Chap 6.4.1) Causal Treatment • Vasoconstriction • Platelet adhesion to endothelial lesion, aggregation, clot formation (primary hemostasis) • Coagulation cascade, fibrinogenesis (secondary hemostasis) • Fibrinolysis Coagulation and fibrinolysis are physiologically balanced and are regulated by activators and inhibitors. The distinction of an extrinsic and intrinsic system is artificial and not relevant for the physiological situation (in vivo). However, it helps to understand in vitro phenomena and clotting laboratory tests (Quick's value, PTT). . Coagulation Disorders • Antithrombin (AT): prevention of excessive thrombin activation by formation of thrombin-AT complex, inhibition of IIa, IXa, Xa, XIa, XIIa; important physiological coagulation inhibitor; AT deficiency constitutes an increased risk of thrombosis (thrombophilia, 7 Chap. 6.6) • Protein C: thrombin-induced conversion into active protein C (APC); APC inhibits FVa and FVIIIa and induces the release of tPA (plasminogenic activator); protein C deficiency constitutes an increased risk of thrombosis (7 Chap. 6.6) • Protein S: cofactor of protein C • Heparin: activation of physiological AT → inhibition of thrombin generation; ineffective in cases of AT deficiency. Unfractionated (UFH) and low molecular weight (LMWH) heparins • Hirudin: direct thrombin inactivation, effective in cases of AT deficiency • Coumarin: vitamin K antagonists; inhibition of the hepatic synthesis of the factors II, VII, IX, and X as well as the proteins C and S • Acetylsalicylic acid: irreversible cyclooxygenase inhibition • Ticlopidine: inhibition of fibrinogen binding by interaction with GPIIb/IIIa • Tirofiban hydrochloride: GPIIb/IIIa receptor antagonist • Dipyridamole: increases the level of cellular cyclic AMP (cAMP) • Clopidogrel: selective inhibition of ADP binding, inhibition of ADP-mediated activation of the GPIIb/IIIa receptor complex Vitamin K Deficiency or Abnormal Synthesis of Vitamin K-dependent Clotting Factors (7 Chap. 6.5.1) • Severe liver damage • Antibiotic treatment, malabsorption syndrome, abnormal fat absorption, alcoholism Coagulopathies which may occur spontaneously or as a result of an underlying disease which is not primarily related to the hemostatic system. In contrast to primary disorders, several components of the hemostatic system are usually affected. Impaired synthesis and metabolic defects can be distinguished. The liver is the primary site of formation and elimination of coagulation factors and their inhibitors as well as filtration → hepatic dysfunction can lead to complex hemostatic disorders: • Impaired synthesis of clotting factors → factor deficiency (esp. factor II, V, VII, IX, X, XIII, fibrinogen, plasminogen, α2-antiplasmin, antithrombin, protein C, protein S) • Impaired elimination of clotting factors → factor excess (e.g., VIII, von Willebrand-factor) • Impaired thrombopoiesis / platelet function (hypersplenism, bone marrow defect due to toxic effects of alcohol, vitamin B12 / folic acid deficiency, thrombopoietin deficiency) • Hyperfibrinolysis • Ascites → loss of coagulation factors (loss of coagulation factors via ascites) • Signs of hepatic failure • Bleeding signs and symptoms: hematomas, mucous membrane hemorrhage, epistaxis • Esophageal variceal bleeding (life-threatening) • Quick's test ↓ (earliest indication of hepatic coagulation defects: includes factor VII which is the first to decrease due to its short half life of 6 h); suitable parameter for monitoring hepatic disorders • aPTT: may be normal or increased in advanced hepatic disorders • Platelets ↓, fibrinogen ↓, factor V ↓, protein C ↓, protein S ↓, antithrombin ↓ (may be increased in case of cholestasis), D-dimers ↑ • Determination of separate factors usually not required • Initial treatment with fresh frozen plasma (FFP) 10 ml/kg. • If insufficient: antithrombin supplementation, fibrinogen supplementation (for levels below 1.0 g/l), administration of cryoprecipitate. • Administration of platelet concentrates, desmopressin (DDAVP; 0.4 µg/kg) and antifibrinolytics (e.g., aprotinin 250,000 IU in 30 min, 2 million IU/day i.v.) may be considered. ATTEN-TION: DIC (7 Chap. 6.5.5) . • If factor XIII concentration < 50% and FFP is without effect: administration of factor XIII concentrate. • If initial values are unknown / emergency situations: empirical treatment with antithrombin 50 IU/kg, fibrinogen 3 g, and PPSB 50 IU/kg. In cases of severe hemorrhage, treatment with activated factor VIIa may be considered. Administration of antifibrinolytics (e.g., tranexamic acid 1 g three times daily), vitamin K Antibodies to clotting factors, occurring as primary (spontaneous) or secondary (due to underlying disease) antibodies: • Autoantibodies − Inhibitors to individual clotting factors (most commonly to factor VIII, antigen-induced hemophilia) − Antiphospholipid antibodies (7 Chap. 6.6) − Monoclonal immunoglobulins, heparin-like antibodies • Alloantibodies (inhibitors in hemophilia A / B replacement therapy) Incidence of factor VIII inhibitors 1:1,000,000 Acquired factor VIII inhibitors: 50% of cases occur spontaneously, secondary inhibitors in conjunction with: Asparaginase therapy of acute leukemias • Impaired synthesis of clotting factors (esp. fibrinogen, antithrombin, protein C and S, factors II, IX, and XIII) • Potential complication: DIC (7 Chap. 6.5.5) Hemorrhages of all degrees and in all locations (hematomas, mucous membrane hemorrhage, postoperative bleeding) Levels of fibrinogen, antithrombin, D-dimers . Acquired Coagulation Disorders Hereditary bleeding disorder caused by deficiency (90% of cases) or inactivity (10%) of coagulation factor VIII (FVIII, AHG-A, antihemophilic globulin A). Most common hereditary coagulopathy, incidence 1 case/5,000 men/year. Women are heterozygotic carriers of the gene. Clinically apparent hemophilia in women is rare. Ratio between hemophilia A and B approximately 5:1. • Factor VIII coding gene located on the X chromosome → mainly men are affected, X-linked recessive inheritance (70% of cases) or spontaneous mutations (30%) • Synthesis in liver, 265 kDa protein, no vitamin K dependence; half-life: 8-12 h • Factor VIII circulates in the plasma bound to von Willebrand factor (vWF) → protection from proteolytic degradation ATTENTION: Treatment must be provided as early as possible and must be sufficient with respect to dosage and treatment period. DDAVP, nasal spray, or intravenous administration (0.3-0.4 µg/kg in 100 ml saline over 30 min, every 12-24 h); effect occurs within 30-60 min: transient FVIII increase by factor 2-3 for up to 4 days; may also be given prior to minor surgery (e.g., tooth extraction), possibly with antifibrinolytics. Administration of recombinant factor VIII or plasma factor VIII. Administration of recombinant factor products excludes the risk of viral contamination (HBV, HCV, HIV, HSV, EBV, CMV, etc. (FEIBA) 20-100 IU/kg body weight every 8-12 h. In emergency situations: plasmapheresis or immunoadsorption Normal life expectancy • Early detection of signs of bleeding • Controlled exercise and sports program to prevent bleeding into joints and to maintain mobility • Avoid platelet aggregation inhibitors (ASS, etc.), no intramuscular injections • Caries prophylaxis, meticulous local hemostasis during surgical procedures; no surgery without prophylactic administration of FVIII • Hepatitis A/B vaccination is recommended • X-linked inheritance → examine coagulation status of patient's relatives Bleeding-related arthropathy often goes unnoticed → close monitoring, permanent FVIII treatment in cases of severe hemophilia: 25-40 IU/kg 1-3 times weekly → rate of complications / arthroplasty significantly decreased. • Severe bleeding / planned operation: increase factor IX for 3 days to > 70% , then keep at > 50% for 7 days • In cases of emergency, fresh frozen plasma (FFP) may be used, if recombinant FIX concentrate is not available • aPTT monitoring is not sufficient, plasma factor IX should be determined (shortly after replacement and before administration of the next dose) • 1-4% of patients develop antibodies against infused factor, with treatment resistance → monitoring via FVII inhibitor assay Normal life expectancy Patient information and instruction (7 Chap. 6.5.2) Bleeding-related arthropathy often goes unnoticed → close monitoring, prophylactic factor IX treatment in cases of severe hemophilia in children: 25-40 IU/kg 2 times weekly → significant decrease of complication / arthropathy rate. Hereditary coagulopathy due to qualitative or quantitative deficiencies of the von Willebrand factor (vWF). D68.0 Most common hereditary coagulopathy, heterozygotic gene carriers 1:100 to 1:1,000; incidence of symptomatic cases: 125 cases/1,000,000 population. Von Willebrand factor is a heterogenic multimeric plasma glycoprotein (normal serum level: 10 mg/l). The vWF precursor is synthesized as a monomer in the endothelium and megakaryocytes. Active forms (vWF multimers) are found in the endothelium, platelets, and plasma. Functions: • Mediation of platelet adhesion to vascular wall (collagen) via high-molecular vWF multimers and binding to platelet glycoprotein Ib (GPIb) • Factor VIII carrier in plasma Hereditary defect caused by mutation in the vWF gene (chromosome 12); autosomal-dominant (subtype 1 and 2) or autosomal-recessive (subtype 2 and 3) inheritance. Consequences: • Impaired platelet adhesion • Reduced FVIII activity Rare: acquired cases due to vWF antibodies in connection with autoimmune diseases, lymphoproliferative diseases, or after multiple transfusions ("von Willebrand syndrome, " VWS). Defects in the vWF-binding glycoprotein GPIb can mimic von Willebrand's disease ("Pseudo-VWD"). Frequency Definition • Type 1: mild form, bleeding time ↑, discrete tendency to bleed, epistaxis, gum bleeding, increased menstruation, bleeding after minor surgery • Type 2: different characteristics depending on subtype; increased soft tissue bleeding, mucous membrane bleeding, gastrointestinal bleeding, hematuria; bleeding into joints less common than with hemophilia; rarely intracerebral bleeding • Type 3: most severe form with pronounced bleeding (soft tissue bleeding, bleeding into joints, and petechial type bleeding) • ATTENTION: in all types life-threatening bleeding may occur up to 14 days after surgery. • Medical history (including family history) • Physical examination including type of bleeding Systemic consumption coagulopathy due to release of coagulation activators, with intracapillary coagulation, microthrombus formation, subsequent ischemic organ damage (kidney, liver, lung) and organ failure. Diffuse tendency to bleed due to collapsed hemostasis with secondary hyperfibrinolysis. Acute DIC is a severe life-threatening disease. Chronic DIC with continuous coagulation may occur in patients with malignant diseases. • Infections: sepsis (gram-negative / gram-positive), malaria, rickettsia, chlamydia, mycobacteria, meningococcus (Waterhouse-Friderichsen syndrome: consumption coagulopathy with adrenocortical bleeding), viral infections • Solid tumors: carcinomas of the lung, pancreas, stomach, colon, prostate, Kasabach-Merritt syndrome (hemangiomas) • Hematological neoplasia: acute promyelocytic leukemia (FAB M3) • Obstetric complications: placenta abruptio, amniotic fluid embolism, septic abortion, eclampsia, postpartal hemolytic-uremic syndrome • Hypoxia and shock: traumatic, hemorrhagic, cardiac, septic • Hemolysis: transfusion errors, toxins, paroxysmal nocturnal hemoglobinuria • Operations on organs with a high thrombokinase content (prostate, pancreas, lung), extracorporeal circulation (contact activation of the endogenous coagulation system) • Trauma: head injury, soft tissue damage, fat embolism • Others: snake bites, heat stroke (endothelial damage), abdominal aortic aneurysms Excessive thrombin synthesis leads to fibrin formation and subsequent intravascular coagulation with consumption of platelets and clotting factors. Inhibitory mechanisms (e.g., inhibition of FVa and FVIIIa via thrombomodulin-activated protein C) cannot compensate the thrombin formation. . DIC Initially (phase I and II), pathological laboratory parameters only. Only with severe consumption coagulopathy (phase III) clinically detectable symptoms: • Hemorrhagic diathesis with ubiquitous bleeding, 75% of cases: skin / mucous membrane bleeding, hematomas, secondary bleeding after venipuncture / from puncture sites, pulmonary hemorrhage, gastrointestinal bleeding, renal bleeding, hematuria, adrenal bleeding / insufficiency, intracerebral bleeding • Multiple microthromboses with impaired organ function, 70%: acute renal failure, impaired liver function, acute respiratory insufficiency (ARDS, "acute respiratory distress syndrome"), intradermal microvascular thrombosis → "purpura fulminans" (skin bleeding with central necrosis), cerebral small vessel ischemia (coma, epileptic seizures) • Shock: tachycardia, decrease in blood pressure, edemas, organ failure • Chronic course: coagulation factor synthesis ↑, thrombosis ↑ → malperfusion of larger blood vessels (embolisms, cerebral ischemia, etc.) • Case history including risk factors • Physical examination I Activation Rapid decrease of platelets, platelet count n / ↓, antithrombin n / ↓, FV n / ↓, FVIII n / ↓, coagulation products ↑ (soluble fibrin, prothrombin fragment F1+2, thrombin-antithrombin complex TAT) II Early consumption Platelets ↓, antithrombin ↓, Quick ↓, coagulation factors (fibrinogen, FV) ↓, PTT ↑, TAT ↑, protein C ↓ III Late consumption Platelets ↓↓ (< 30,000/µl), antithrombin ↓↓, Quick ↓↓, coagulation factors ↓↓ (fibrinogen, FV, and FVIII), PTT ↑↑, thrombin time ↑↑, fibrinogen degrading products / fibrin monomers +, D-dimers +++, detectable fragmentocytes IV Recovery Decrease in coagulation products (soluble fibrin, prothrombin fragment F1+2, TAT), increase of clotting factors (fibrinogen, FV, FVIII), normalization of global clotting tests n normal, F factor, TAT thrombin-antithrombin complex, PTT partial thromboplastin time • Basic diagnosis: platelets (platelet decrease often first symptom), antithrombin, D-dimers, fibrinogen, Quick's test, PTT • Advanced diagnosis: fibrin monomers (soluble fibrin), prothrombin fragments F1+2, thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex, factor V, protein C, possibly protein S (in cases of purpura fulminans) Basic screening test Score A score ≥ 5 indicates ongoing DIC; with scores < 5 diagnostics should be repeated every 12-24 h depending on the individual clinical condition. • With tumors / infections / pregnancy, the platelet count is often increased ("reactive thrombocytosis") → normal platelet counts may already indicate DIC. • Fibrinogen is an acute-phase protein → "normal" fibrinogen levels may already be pathologically decreased (e.g., with infections). • With DIC, frequent monitoring is required to determine the dynamics and course of disease. • Primary hyperfibrinolysis: normal platelet count, normal ATIII, no fibrin monomers Basic therapy • Antithrombin (AT) replacement if AT level < 70% (initially 1,000 IU, then 500 IU every 6 h), check level (target: 80-100%) • Heparin: 100-300 IU/kg/day (not with AML type M3 or patients with high bleeding risk), depending on platelet count Organ dysfunction, bleeding • Fresh frozen plasma (FFP, 10 ml/kg) • Antithrombin (AT), 500-1000 IU every 6 h • Fibrinogen replacement with fibrinogen levels of < 100 mg/dl • Platelet transfusion (target: > 50,000/μl) • Red cell transfusion according to hemoglobin level, compensation of acidosis • Heparin is contraindicated, no intramuscular injections • Patients should be treated in intensive care unit • Severe uncontrollable bleeding: administration of activated FVIIa. ATTENTION: potential risk of thromboembolic complications ATTENTION: administration of coagulation factors can increase DIC and should be avoided. For replacement therapy, use fresh frozen plasma (FFP). • Severe sepsis: activated protein C (drotrecogin) 24 µg/kg/h over 96 h → decreases mortality from 31% to 25%. ATTENTION: with thrombocytopenia higher risk of hemorrhagic complications. Contraindicated after brain hemorrhage, epidural catheter, etc. • In DIC, avoid fibrinolysis inhibitiors: → in cases of uncontrollable bleeding: use aprotinin (e.g., 250,000 units in the first half hour, followed by 2 million units/day), platelets, fibrinogen, and PPSB. In cases of life-threatening bleeding or lack of success: administer recombinant FVIIa. • Fibrinolysis inhibitors (antifibrinolytics, e.g., tranexamic acid) may be indicated with hyperfibrinolytic conditions (prostate carcinoma, AML M3) in phase I of a DIC only. • Low-dose heparinization is indicated in cases of: purpura fulminans, acral ischemia, venous thrombosis. For phase I, some studies favor low-molecular weight heparin (100-200 units/kg/ day). • Clinical monitoring: close monitoring of neurological, cardiovascular, respiratory and renal parameters • Monitoring of bleeding: tachycardia, hemoglobin decrease, retroperitoneal bleeding (→ sonography), neurology • Laboratory tests: coagulation parameters, blood count, hepatic and renal function parameters, electrolytes Dd: Dd: Th: Th: . DIC platelet aggregation inhibitors (acetyl salicylic acid, ticlopidine, clopidogrel) New therapies for ITP Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and pregnancy AMG 531, a thrombopoiesis stimulating protein, for chronic ITP Management of adult idiopathic thrombocytopenic purpura Idiopathic thrombocytopenic purpura: a guideline for diagnosis and management of children and adults Long-term outcomes in adults with chronic ITP after splenectomy failure Morbidity and mortality in adults with idiopathic thrombocytopenic purpura Long-term observation of 208 adults with chronic idiopathic thrombocyto--Argatroban: direct thrombin inhibitor, interacts with the active site of thrombin. Half-live 24 min., monitored by PTT. No dose adjustment in renal failure • In cases of existing thrombosis: coumarin overlapping with danaparoid or hirudin. • Avoid using LMWH How I treat heparin-induced thrombopenia and thrombosis Heparin-induced thrombocytopenia British Committee for Standards in Haematology. The management of heparin-induced thrombocytopenia Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation Delayed-onset heparin-induced thrombocytopenia Cancer-related anemia: pathogenesis, prevalence and treatment EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer Guidelines for the clinical use of red cell transfusion The impact of hemoglobin levels on treatment outcomes in patients with cancer Red cells I: inherited anaemias Red cells II: acquired anemias and polycythaemia ASH/ASCO 2007 clinical practice guideline update on the use of epoetin and darbepoetin Modern treatment of thalassaemia intermedia British Committee for Standards in Haematology. Guidelines for the diagnosis and management of hereditary spherocytosis Hereditary elliptocytosis: spectrin and protein 4.1R Management of cold haemolytic syndrome The complement inhibitor eculizumab in PNH Treatment of autoimmune hemolytic anemia Glucose-6-phosphate dehydrogenase deficiency Sickle-cell disease Recessively inherited coagulation disorders Mechanisms of disease: the impact of antithrombotic therapy in cancer patients Coagulation Disorders • FFP 10 ml/kg (coagulation factor increase by • Antithrombin concentrate: 20 IU/kg → increase by approximately Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors The antiphospholipid syndrome Identification of the gene for vitamin K epoxide reductase Rituximab in the treatment of acquired factor VIII inhibitors Treatment of acquired hemophilia by the Bonn-Malmö protocol Immune tolerance induction: recombinant vs. human-derived product Haemophilia 2002: emerging risks of treatment Haemophilia A: from mutation analysis to new therapies Recombinant activated factor VII in patients at high risk of bleeding Dose and response in haemophilia: optimization of factor replacement therapy Comparing outcomes of different treatment regimens for severe haemophilia Consensus perspectives on prophylactic therapy for haemophilia: summary statement Inhibitor development in haemophilia B Recombinant activated factor VII in patients at high risk of bleeding Dose and response in haemophilia: optimization of factor replacement therapy Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B Prg: Prg: Px: Px: Ref: Ref: Web: Web Ref: Web: Web: In cases of manifest severe DIC: 50-80% mortality Administration of heparin 10 Efficacy and safety of recombinant human activated protein C for severe sepsis The prothrombotic state in cancer: pathogenetic mechanisms Update on the treatment of disseminated intravascular coagulation Disseminated intravascular coagulation: what's new? DIC 2002: a review of disseminated intravascular coagulation High dose antithrombin III in severe sepsis DIC in acute leukemia: clinical and laboratory features at presentation Thrombosis: localized intravascular aggregation of blood components → thrombus (clot) formation with consecutive vascular occlusion Embolism: migration of detached thrombus (clot) elements in the blood stream with consecutive vascular occlusion. Triggers: thrombotic material, tumor particles or leukemic cell thrombi, sclerotic material, fat droplets, amniotic fluid, air. Thrombophilia: increased risk of occurrence of thromboembolic events Thrombosis incidence: 3 cases/1,000 population/year; location: > 90% in inferior vena cava or leg / pelvic veins; male:female = 1:1; particularly in patients > 50 years of age Idiopathic" deep vein thrombosis or pulmonary embolism in clinically "healthy" adults is due to an underlying malignancy in 6-35% of cases Pulmonary embolisms or venous thromboses are found in up to 50% of cancer patients at autopsy Virchow Triad: Major Pathomechanisms of Thrombogenesis • • • Endothelial alterations: vascular sclerosis, inflammation, trauma, etc. Circulation disorders: intravascular stasis, vortex formation Endothelial Alterations (esp. with Arterial Thrombosis) phlebitis Circulation Disorders • Immobilization, bed rest • Intravascular stasis due to vascular constriction or compression: e.g., after extended periods of travel ("economy class syndrome"), varicosis, obesity, pregnancy, solid tumors, or lymphomas • Altered blood flow due to cardiac disorders Hypercoagulability Thrombocytosis E.g., myeloproliferative syndromes (7 Chap. 7.3) Def: Def: ICD-10: ICD-10: Ep: Ep: Pg: Pg: . Thromboembolism and Thrombophilia APC (activated protein C) resistance: most common cause of thrombophilia; in 95% of cases due to factor V mutations → abnormal APC binding site (mainly point mutations in the factor V gene, G1691A, "factor V Leiden") → insufficient inactivation of factor V by mutated APC. Prevalence: heterozygotic carriers 3-9% of normal population, 20-40% among patients with thrombosis. Relative thrombosis risk in heterozygotic cases approximately 3-to 7-fold, in homozygotic cases 50-to 100-fold increased. Other causes (< 5%) for APC resistance: antiphospholipid antibodies, oral contraceptives, pregnancy. Factor II mutation: prothrombin mutation G20120A, often associated with increased prothrombin levels. Prevalence: heterozygotic carriers 2-4% of normal population; among patients with thrombosis 5-7%. Relative risk of thromboembolisms: 2-to 4-fold increased. Factor VIII increase: 25% of thrombosis patients show persistent FVIII increase of unknown etiology Antithrombin / protein C / protein S defects: rare hereditary disorders; AT deficiency especially is associated with a high risk of thrombosis. DD: hepatic diseases. Hyperhomocysteinemia: hereditary defect of cystathionine β synthetase; or acquired due to vitamin B6, B12, or folic acid deficiency. Antiphospholipid syndrome: most common acquired form of thrombophilia; occurs as primary or secondary (as a result of systemic lupus erythematosus SLE, collagenosis, malignancy, medication, infections) subtype − Rapid onset of the anticoagulation effect; minimal laboratory monitoring required (platelet count during first 3 weeks, antifactor Xa levels in patients with renal failure, cachectic, or overweight patients) hemorrhagic complications, osteoporosis, and heparin 000 IU bolus > 70 kg; then continuous intravenous treatment: 30,000 IU/24 h, maximum 50,000 IU/24 h; dosage according to PTT: target PTT > 60-90 s, first PTT test after 6 h, then every 12 h; once stable, it is sufficient to check PTT once daily • Alternatively, subcutaneous administration: 7,500-10,000 IU s.c. 3 times daily; studies have shown that with identical PTTs, intravenous and subcutaneous administration are equally effective • Side effects: hemorrhage (in up to 10% of patients), hypersensitivity (urticaria, bronchospasm, fever, even shock), alopecia (rare), vasospasm (rare), osteoporosis (with long-term use), heparin-induced thrombocytopenia • Arterial occlusion (extremity arteries, acute myocardial infarction Discontinuation of Heparin Treatment • Adoption of coumarin: discontinuation of heparin treatment once target INR is reached (usually after 5 days); exception: in cases of extensive thrombosis (calf to pelvis), continue heparin treatment for 10-14 days • Absence of contraindications and patient compliance provided, LMWH treatment may be possible in an outpatient setting Effect Vitamin K antagonism → inhibition of the hepatic synthesis of coagulation factors F II, VII, IX, X of age, hemorrhagic diathesis, sepsis • Uncompensated hypertension, liver or renal insufficiency • Surgery within last 7-10 days, arterial puncture, intramuscular injections • CNS surgery within the last 3 months, cerebral bleeding, cerebral sclerosis, CSF puncture within the last 10 days • Pancreatitis, endocarditis lenta, diabetic retinopathy, nephrolithiasis • Pulmonary / gastrointestinal diseases with high risk of bleeding Recommendations from the British Committee for Standards in Haematology and National Patient Safety Agency British Committee for Standards in Haematology (BCSH). Guideline. Investigation and management of heritable thrombophilia Prophylaxis for thromboembolism in hospitalized medical patients The effect of low molecular weight heparin on survival in patients with advanced malignancy Deep vein thrombosis Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism Deep venous thrombosis ASCO Guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer Hereditary coagulopathy due to deficiency or inactivity of coagulation factor IX (FIX, Christmas factor, antihemophilic globulin B, AHG-B). Rare hereditary coagulopathy, incidence 1 case/25-30,000 men/year. Women are heterozygotic carriers of the gene.• Factor IX coding gene is located on the X chromosome → mainly men are affected, X-linked recessive inheritance; hereditary forms (80% of cases) and spontaneous mutations (20%) • Hepatic synthesis, 55 kDa protein, vitamin K-dependent, half-life 24 h • Mild bleeding: vasopressin analog desmopressin (DDAVP), nasal spray or intravenously, e.g., every 12-24 h 0.3 µg/kg body weight i.v. in 100 ml saline 0.9% over 30 min → release of vWF in endothelium, increase of the vWF level by factor 3-5. Response within 30-60 min in > 80% of patients; duration of effect 8-10 h. Since not all patients respond, conduct provocation test prior to treatment; treatment must be interrupted after 3-5 days due to depletion of endogenous vWF stores. • With menstruation, single doses of DDAVP prior to menstruation are usually sufficient; supportive estrogen therapy with subtype 1. • Severe bleeding: similar strategy to type 2B, 2N, and 3. • Administration of high-vWF plasma products (e.g., 20-70 U/kg 2-4 times daily or 3-5 U/kg/ h per infusor) until ristocetin cofactor activity > 60% for at least 72 h. ATTENTION: Recombinant FVIII products contain no vWF and are ineffective in von Willebrand's disease → use special high-vWF plasma or FVIII products. • Platelet concentrates • If surgery is planned: vWF antigen as well as ristocetin cofactor activity should be 60%, pre-as well as postoperatively. • ATTENTION: With subtype 2B, DDAVP did not demonstrate a clear benefit (risk of thrombocytopenia). With subtype III, it is ineffective. • Monitoring of vWF antigen, FVIII function (FVIII:C), ristocetin cofactor (RiCof) according to disease subtype.Th: Th:. Von Willebrand's Disease• Development of vWF alloantibodies in 10-15% of cases, risk of anaphylactic reactions with repeated exposure. With neutralizing antibodies and bleeding complications factor VIIa may be given. • If DDAVP has proven to be effective, give 30 min prior to surgery • High risk of hemorrhage (e.g., tonsillectomy): raise vWF antigen and ristocetin cofactor activity up to 60%; administer high-vWF FVIII concentrate • Intraoperative use of fibrin glue and fibrinolysis inhibitors (e.g., tranexamic acid mouthwash with dental surgery) • During pregnancy, hormone-induced increase in vWF and FVIII:C → with subtype 1 and 2 no further treatment required • Peripartum: keep vWF antigen and Ristocetin cofactor activity above 50%; with cesarean section, aim for 100% pre-and postoperatively • Vessel wall defects: endothelial alterations due to intravascular catheters / lines, antineoplastic treatment, direct invasion of tumor tissue; cytokine-mediated activation of the endothelium → enhanced expression of tissue factor / adhesion molecules / PAI and decreased endothelial thrombomodulin expression → thrombophilic surface • Changes in blood flow: immobilization, tumor-related vascular compression, stasis, hyperviscosity • Changes in coagulation system: fibrinogen ↑, factor V ↑, FVIII ↑, von Willebrand factor ↑, FXII ↑, AT ↓ • Release of procoagulating substances ("cancer coagulants, " e.g.,tissue factor = TF, FX activators) with activation of the extrinsic system via factor VII or direct FX activation; high levels of TF in promyelocytes of acute leukemia type FAB M3 • Decrease in coagulation inhibitors (antithrombin, protein C and S) due to chemotherapy (asparaginase) • Swelling of the arm, hyperthermia, livid discoloration, tightness • Pain in forearm, upper arm and/or shoulder, fever veins, mesenteric veins); thromboembolic event despite effective anticoagulation; thrombosis during pregnancy and tendency to miscarriage and stillbirth − Analysis of: fibrinogen, antithrombin, protein C, protein S, prothrombin (FII), FVIII, APC resistance, factor II mutation, antiphospholipid antibodies (lupus anticoagulants, anticardiolipin antibodies), plasminogen deficiency − Extended diagnostics: homocysteine, methyltetrahydrofolate reductase (MTHFR) mutation G77T, FIX, and FXII − In most cases, repeated tests are required. With suspected thrombophilia, patients should be referred to specialized hematology centers. • Venous thrombi → pulmonary embolism (in > 95% of cases due to phlebothrombosis, approximately 50% of patients with phlebothrombosis develop pulmonary embolism) • Arterial / cardiac thrombi → cerebral malperfusion, renal infarction, extremities • Post-thrombotic syndrome (after 10-15 years, in 40-60% of conventionally treated patients) • Chronic leg ulcer (in 10% of patients) • Effect: factor Xa inhibition, half-life: 100-180 min • Dosage: enoxaparin 1 mg/kg twice daily s.c., dalteparin 100 IU/kg twice daily, or tinzaparin 175 IU/kg once daily • Advantages of treatment with LMWH compared to UFH: According to INR ("international normalized ratio"). In normal weight patients (≈ 70 kg), the following rule of thumb applies: current Quick value divided by 10 is the number of coumarin tablets to be given in the first 4 days. On day 1, give 3 tablets, on days 2 and 3 give 2 (or 1) tablets (slow initiation to reduce the risk of coumarin necrosis). The INR should be checked on day 4. The result determines the dosage of subsequent treatment. Heparin treatment may be discontinued once the target INR has been reached (usually after 5-6 days). The duration of anticoagulation treatment has to be determined individually for each patient, based on thrombosis type, location, risk factors and comorbidities. Guideline: Patients with contraindications against coumarin may receive low molecular weight heparin as secondary prophylaxis on a long-term basis. Half the therapeutic LMWH dose is usually recommended (comparable to an INR of 2-3); start after 10-14 days of "full dose" therapeutic LMWH treatment. Cancer patients in particular benefit from treatment with low molecular weight heparin. Due to frequent occurrence of hemorrhagic complications (10-15%), increased mortality (1-2%) and limited long-term benefit (no reduction in occurrence of post-thrombotic syndrome), fibrinolysis now only plays a secondary role. An indication for treatment with fibronolytics (e.g., streptokinase, urokinase) may exist in young patients with extensive fresh thrombosis. Surgical thrombectomy allows immediate perfusion of the blood vessel. However, endothelial injury and incomplete thrombus removal often lead to rapid reformation of thrombi. Indications: • Phlegmasia cerulea dolens • Fresh isolated descending pelvic vein thrombosis (not older than 1-2 days) • Acute arterial occlusion Placement of a filter in the V. cava reduces the risk of severe pulmonary embolism in patients with recurrent thromboses. Indications are:• Recurrent pulmonary embolism despite effective anticoagulation • Contraindication against anticoagulants • Immobilization: studies did not confirm a role for immobilization in the prevention of pulmonary embolisms. • In patients with severe pain or edema: elevation and immobilization of the leg for a limited number of days. • Compression therapy: compression dressings with bandages or compression stockings; contraindicated with peripheral arterial occlusive disease and phlegmasia cerulea dolens. Compression stockings should be worn for at least 2 years as secondary prophylaxis after DVT of the lower extremity. In most cases, calf compression stockings on the affected leg are sufficient.• Anticoagulants • Platelet aggregation inhibitors, acetylsalicylic acid 100 mg daily p.o. (protective effect in particular with arterial occlusion and coronary heart disease) • Elimination of risk factors (see above), early postoperative mobilization, physiotherapy, compression stockings