Coagulation Disorders 2024 PDF

COAGULATION DISORDERS  INHERITED COAGULATION DISORDERS: OVERVIEW HEMOPHILIA 1. Hemophilia A = FVIII 2. Hemophilia B = FIX von WILLEBRAND’S disease 3. Type 1-3 4. lack / no production of vWf  HEMOPHILIA Also known...

COAGULATION DISORDERS  INHERITED COAGULATION DISORDERS: OVERVIEW HEMOPHILIA 1. Hemophilia A = FVIII 2. Hemophilia B = FIX von WILLEBRAND’S disease 3. Type 1-3 4. lack / no production of vWf  HEMOPHILIA Also known as “love of bleeding” Bleeding manifestations of both (A & B) are identical Cannot differentiate clinically Hemophilia A from Hemophilia B Some infants are asymptomatic until they become active toddlers and experience minor trauma. Loading… Bruising easily in early childhood spontaneous bleeding (particularly into DEEP TISSUE such as the joints, muscles, and soft tissues) life-threatening bleeding after trauma or surgery. results in lifelong bleeding problems.  HEMOPHILIA A Bleeding due to deficiency of FVIII coagulant activity Severity of bleeding is related to FVIII level in blood Low levels of FVIII (< 1 iu/dL) Frequent bleeding, spontaneous bleeding joints or muscle Transmitted as RECESSIVE X-LINKED INHERITANCE Males affected, Females carriers Affect mutation of Gene for FVIII production The defect is an absence / low level of plasma factor VIII  MALE AFFECTED Loading… FEMALE CARRIER  CLINICAL FEATURES OF HEMOPHILIA A Infants – may develop joint and soft tissues bleeds and excessive bruising when they start to be active Dental eruption – prolonged bleeding after dental extraction Hemarthrosis – recurrent and painful joints bleed hematomas – Poorly treated lead to joint deformity and disability – trauma with walking Hemophilic pseudo tumor – rare complication of hemophilia consisting of a progressive cystic swelling of muscle and/or bone due to repeated bleeding Hematuria Gastrointestinal bleeding Recurrent hemarthrosis causes joint deformity and disability  CLINICAL FEATURES OF HEMOPHILIA A SEVERITY OF HAEMOPHILIA A RELATES TO FACTOR VIII LEVEL D - Tomor prothrombic Time - Thrombine Time (t) (cot)  Laboratory investigations (haemostasis tests) for HA The initial laboratory work includes : complete blood count. prothrombin time (PT) i. partial thromboplastin time (PTT) v. bleeding time (BT). In both hemophilia A and B, PTT will be prolonged (intrinsic pathway disruption), whereas PT and BT will be normal. Once PTT is found to be prolonged, it should be followed by a mixing study. In a mixing study, the PTT should normalize if factor deficiency is suspected. After the mixing study, the next step should be factor VIII. Hemophilia is usually the diagnosis if the factor activity is less than 40% of normal factor activity. Molecular genotyping should then be offered to confirm the diagnosis and also to help predict disease severity. OTHER LABORATORY INVESTIGATION CARRIER DETECTION AND ANTENATAL DIAGNOSIS 1. Measuring plasma levels of factor VIII 2. DNA probes – detect mutation in carriers 3. Loading… 8-10 weeks gestation biopsies – fetal DNA for analysis 4. Antenatal diagnosis – FVIII in fetal blood at 16-20 weeks gestation from UV- ultrasound guided needle aspiration  TREATMENTS Factor VIII replacement therapy (using recombinant factor or from frozen plasma concentrate) Desmopressin – a synthetic vasopressin analogue which stimulate releases of FVIII and vWF stores from endothelial cells, boosting plasma levels. Prophylactic treatments – stored FVIII at home. Prophylactic treatment can reduce the frequency of cerebral and muscle bleeds and reduce the need for hospitalizations. It helps improve the quality of life for patients.  Social and physiological care NON GENETIC FORM OF HEMOPHILIA A caused by autoantibodies against factor VIII and so is known as acquired haemophilia A. Acquired haemophilia can be associated with cancers, autoimmune disorders / response to treatment and following childbirth.  HEMOPHILIA B Haemophilia B / Christmas disease / Factor IX deficiency Inheritance & clinical features – identical to HA FIX is coded by a gene close to FVIII gene HB only distinguishable from HA by specific coagulation assays Incidence – 1/5 of HA Carrier & antenatal diagnosis – similar as HA. However, it is important to note that factor IX levels can be low at birth as it takes about six months for babies to reach their normal levels. Therefore umbilical cord blood samples are more accurate in finding lower levels of factor VIII, while low levels of factor IX at birth in umbilical cord blood samples do not indicate the presence of hemophilia B.  HEMOPHILIA B TREATMENTS infusion FIX – longer half life than FVIII – less frequent infusion LABORATORY FINDINGS Abnormal 1. prolonged APTT 2. reduced FIX Clotting assay Normal 3. Bleeding time 4. PT  ADDITIONAL INFO : HEMOPHILIA 1. Hemophilia is a hereditary disease but NOT ALWAYS associated with family history. 2. Hemophilia can develop due to spontaneous mutation affecting either F8 or F9 gene. 3. It is almost always due to a defect or mutation in the gene for the clotting factor. 4. Research has identified over 1000 mutations in the genes encoding factor VIII and IX, and around 30% are due to spontaneous mutation. 5. Female MOSTLY appear as carrier presented with or without symptom 6. Female can suffer hemophilia but very rare. VON WILLEBRAND’S DISEASE 1. Abnormalities due to either reduced level or abnormal function of vWf due to point mutation / major deletion 2. vWf is large proteins (300 kDA) – forms multimers 3. Inheritance is autosomal dominant 4. Typically mucous membrane bleeding (nose & gum bleed), bleeding after dental extraction, post- traumatic hemorrhage. 5. Severity is variable depending of type of VWD  VON WILLEBRAND’S DISEASE vWF- dwifunctional proteins : 1. promotes platelet adhesion to damaged endothelium and subsequently platelet aggregation 2. as carrier molecule for FVIII – protecting from premature destruction of FVIII. Thus there is reduced FVIII in vWD disease  VON WILLEBRAND’S DISEASE vWD 3 types 1. Type 1 – reduced vWF – milder form of VWD 2. Type 2 – abnormal form of vWF proteins (vWF can’t function properly) 3. Type 3 – very little or total lack of vWF – most severe form of VWD Type 2 : 4 subtypes 4. 2A: Loss of HMW multimers, thus vWF is not the right size and doesn’t help platelet aggregation 5. 2B: vWF has abnormally high affinity for platelets (when there is no injury) causing abnormal vWF attachment to platelet. Body will  VON WILLEBRAND’S DISEASE LABORATORY FINDINGS IN HEMOSTATIC TESTS. Prolonged bleeding time Low FVIII prolonged aPTT Low vWF Defective platelet aggregation Platelet count is normal except low in type 2B  SPECIALIZE LAB INVESTIGATION FOR VWF:Ag VWD 1. an immunoassay 2. measures the concentration of vWf protein in plasma VWF:RCo 3. functional assay of vWf 4. Measure its ability to interact with normal platelets 5. Antibiotic namely ristocetin causes VWF to bind to platelets, resulting in platelet clumps 6. Indicate ability of vWf to promote platelet aggregation  VON WILLEBRAND’S DISEASE TREATMENTS Antifibrinolytic agent- for type 2B Desmopressin – for Type 1 vWD FVIII and vWF infusion for patients with very low vWf levels  HEMOPHILIA A VERSUS VWD THE DIFFERENCES: GENDER 1. HA = Male is mostly affected 2. VWD = Both can be equally affected BLEEDING SYMPTOMS 3. HA = Common for Deep tissue bleeding and musculoskeletal; eg joint and internal organs 4. VWD = Common for mucosal bleeding (mucocutaneous), rare deep tissue bleeding. This is because the von Willebrand factor targets skin and mucous membranes like linings of the nose, mouth, vagina, uterus, intestines, etc., and that is why its deficiency  primarily causes nosebleeds, gum bleeds, easy bruising, heavy ACQUIRED COAGGULATION DISORDERS More common than inherited disorders Involvements of multiple clotting factors deficiencies  VITAMIN K DEFICIENCY 1. Due to inadequate diet 2. Malabsorption 3. Inhibition of vitamin K by drugs such as warfarin (Vitamin K antagonist) 4. Warfarin – associate with decreased in functional activity of factors II, VII, IX and X and protein C & S 5. Deficiency may present in the newborn – known as hemorrhagic disease of the newborn  HAEMORRHAGIC DISEASE OF THE NEWBORN 1. Vitamin K deficiency due to liver cell immature (cannot absorb vit. K), lack gut bacterial synthesis, low quantities in breast milk 2. Lead to hemorrhage Laboratory findings 3. Prolonged PT and aPTT 4. Normal - Platelet count and fibrinogen 5. Deficiency of the vitamin K dependent procoagulant factors II, VII, IX, X. TREATMENTS VITAMIN K DEFICIENCY IN CHILDREN / ADULTS Due to obstructive jaundice, pancreatic or small bowel disease Laboratory findings Prolonged PT and APTT Normal - Platelet count and fibrinogen Deficiency of the vitamin K dependent procoagulant factors II, VII, IX, X. TREATMENTS Prophylaxis : oral vitamin K HEMOSTASIS DISORDERS IN LIVER DISEASE VIT K COAGULATION ABSORPTION FACTORS SYNTHESIS TROMBOPOIETIN LEAD TO FIBRINOGEN SYNTHESIS (acquired THROMBOCYTOPENIA dysfibrinogenaemia) DIC DUE TO SECRETION OF SYNTHESIS OF COAGULATION INHIBITORS – THROMBOPLASTIN BY DAMAGED PROMOTE DIC LIVER CELLS  LIVER DISEASE 1. Biliary obstruction - impaired absorption of Vit K - decreased synthesis of factors II, VII, IX , X by liver parenchymal cells Loading… 2.Severe hepatocellular disease 3.Functional abnormality of fibrinogen (dysfibrinogenaemia) found in many patients 4.Decreased thrombopoietin production from liver contributes to thrombocytopenia 5.DIC – a result from release of thromboplastin from damaged liver cells and reduced concentrations of antithrombin, protein C and α2-  DISSEMINATED INTRAVASCULAR COAGULATION 1. Widespread intravascular deposition of fibrin + over consumption of coagulation factors & platelets 2. A result of many disorders that release procoagulant material into circulation and induce endothelial damage + activation of hemostasis pathway.  DISSEMINATED INTRAVASCULAR COAGULATION PATHOGENESIS Entry of procoagulant into circulation following : - amniotic fluid embolism - liver disease - premature separation of placenta - cancer cells - snake bites - endothelial damage - infections – immune response – vasculitis - severe burns  DISSEMINATED INTRAVASCULAR COAGULATION LABORATORY FINDINGS 1. Low platelet counts 2. Prolonged TT, PT and APTT 3. Increased D-dimers or Fibrin degradation product (FDP) in serum 4. Hemolytic anemia and RBC fragmentation – damage due to presence of mini-thrombus and fibrin strands in small vessels that obstruct circulation.  DISSEMINATED INTRAVASCULAR COAGULATION TREATMENTS 1. Fresh frozen plasma OR plasma concentrate 2. RBC transfusion 3. Antithrombin & protein C to inhibit DIC COAGULATION DEFICIENCY CAUSED BY ANTIBODIES Alloantibodies to factor VIII in 5-10% hemophilia cases – causing bleeding syndrome SLE –autoimmune disease- lupus anticoagulant – interfere with coagulation TREATMENT: Immunosuppression or factor replacement  MASSIVE TRANSFUSION SYNDROME Further dilution of reduced platelets, coagulation and inhibitors levels 24-hr blood storage at 4°C – platelet aggregation, poor function & low counts Some patients may have a pre-existing bleeding disorders