Bleeding Disorders Flashcards
Assessment of intrinsic pathway
- partial thromboplastin time (PTT or APTT)
Assessment of extrinsic pathway
- prothrombin time (PT)
How to do prothrombin time
- add thromboplastin and calcium to plasma
Prothrombin time uses
- monitor warfarin (coumadin) therapy
- evaluate liver disease
- evaluate vitamin K deficiency
- evaluate disseminated intravascular coagulation (DIC)
International normalized ratio (INR)
- uses international sensitivity index (ISI) to normalize PT time
- ISI=measure of the sensitivity of the thromboplastin the lab is using
How to do PTT
- add activator, calcium, & phospholipid to plasma
Reasons for prolonged PTT
- heparin
- factor deficiency that may cause bleeding
- factor deficiency w/ no clinical significance (factor XII)
- specific factor inhibitor - most commonly to factor VIII
- antiphospholipid antibody
Mixing study
- used in evaluation of a prolonged PTT or PT
- patients sample mixed w/ equal volume of normal plasma
- correction to normal = FACTOR deficiency
- continued prolongation = INHIBITOR (aka antibody)
Fibrinogen
- measured by addition of thrombin to plasma
- may have either quantitative or qualitative abnormalities of fibrinogen
- DECREASED in DIC, liver disease, congenital absence of fibrinogen
D-dimer
- D-dimer assay detects excess generation of cross linked fibrin by plasmin
- useful in evaluation of DIC
- used in evaluation of venous thrombosis & pulmonary embolism
PFA-100 closure times
- evaluates platelets
1. col/epi & col/ADP - normal = no platelet abnormality
2. col/epi long & col/ADP normal = aspirin effect
3. col/epi & col/ADP abnormal = platelet defect or von willebrand disease
Causes of hemorrhage
- trauma, tumor, ulcer, necrosis, depletion of hemostatic factors
Petechia
- pinpoint hemorrhages in skin
- sign of platelet disorder
Purpura
- slightly larger hemorrhages than petechia
Ecchymoses
- large areas of hemorrhage into skin
- aka large bruises
Hematoma
- localized collection of clotted blood into a space or potential space
Platelet
- produced in marrow from megakaryocytes
- normal number 150,000-450,000/uL
- remain in circulation 7-10 days
- QUANTITATIVE problems more common than qualitative
- typically causes mucocutaneous bleeding
Platelet counts & bleeding risk
- minimal bleeding: >50,000
- minor bleeding: 20-50,000
- spontaneous:
Thrombocytopenia causes
- decreased platelet production
- ineffective platelet production
- splenic sequestration of platelets
- increased peripheral destruction
Bone marrow appearance in aplastic anemia
- all FAT no cells
Increased platelet destruction causes
- non immune destruction: DIC, other microangiopathic hemolytic anemias
Immune mediated thrombocytopenia
- alloimmune destruction: maternal fetal incompatability, blood transfusion
Drug induced thrombocytopenia
- drug or metabolite attached to platelet surface
- development of antibodies to platelet-drug complex
- platelets removed by macrophages in liver/spleen
- QUININE is prototypic drug
Heparin induced thrombocytopeina
- caused by antibody directed against heparin & platelet factor 4
- causes platelet AGGREGATION & thrombocytopenia
- may cause life threatening THROMBOSIS
Acute immune thrombocytopenia purpura
- CHILDREN: 2-6 yrs old
- antecedent viral illness
- increased incidence in fall/winter
- ABRUPT onset
- self limited course, most completely recover
- Rx: steroids, IV IgG, Rh immune globulin
Chronic immune thrombocytopenia purpura
- ADULTS: 20-40 yrs old
- FEMALES greater than males, 3:1
- GRADUAL onset
- remission and RELAPSES over years
Thrombotic thrombocytopenia purpura
- PENTAD of features: microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever, renal dysfunction
TTP histologic findings
- thrombi w/in glomerular capillaries
- schistocytes in peripheral blood
TTP etiology & treatment
- deficiency of a protease (ADAMTS13): cleaves large von willebrand multimers
- multimers aggregate platelets leading to thrombi
- treatment: plasmapheresis & infusion of fresh frozen plasma
- *FATAL unless they undergo treatment**
Drug induced platelet dysfuntion
- aspirin: IRREVERSIBLY acetylates COX
- NSAIDs: REVERSIBLY inhibit COX
- clopidogrel: blocks ADP receptor (P2Y12)
Disease-related platelet dysfunction
- uremia: global platelet dysfunction
- paraproteins (plasma cell myeloma)
- myeloproliferative disorders
- after extracorporeal platelet circulation (cardiac bypass pump)
Hemophilia A (classic hemophilia)
- factor VIII deficiency
- sex linked: men effected, women carriers
- incidence: 1/10,000 males
- MOST common hereditary disease
- most severe hemophiliacs have inversion mutation in X chromosome
Type of bleeding with hemophilia
- bleeding into JOINTS, hematomas
Signs & symptoms of severe hemophilia
- delayed bleeding from small wounds b/c platelets are normal
- hematomas, hemarthrosis, hematuria
- joint destruction & muscle atrophy
- death from bleeding into vital areas, complications of therapy
- lab abnormalities: prolonged PTT, normal PT, normal PFA-100
Treatment of hemophilia
- treatment of hemophilia A is factor VIII replacement
- 5-15% of patients will develop factor VIII inhibitor (antibody)
Hemophilia B
- factor IX deficiency
- sex linked, incidence: 1/50,000 males
- cause: failure of synthesis or synthesis of defective factor IX
- treatment: factor IX
- lab abnormalities: prolonged PTT, normal PT
Other coagulation factor deficiencies
- most are rare
- deficiency in factor XII: benign disorder, NO increased risk of bleeding, prolonged PTT
Von willebrand disease
- autosomal dominant
- deficiency of von willebrand factor
- relatively common (1% population): bleeding occurs in less than 10% of these patients
- signs/symptoms: mucocutaneous bleeding, epistaxis, menorrhagia
Diagnosis of von willebrand disease
- prolonged PFA-100 closure time
- decreased factor VIII level
- decreased von willebrand factor antigen activity
Subtypes of von willebrand disease
Type I: 70% moderate reduction in vWF levels in plasma
Type II: qualitative defects in vWF
Type III: autosomal recessive-vWF absent, present like hemophiliacs
Treatment of von Willebrand disease
- avoid aspirin
- DDAVP (desmopressin), synthetic analog of vasopressin
- humate P: contains factor VII and vWF
Changes in hemostasis in liver disease (vWF & factor VIII)
- increased levels of vWF & factor VIII due to endothelial cell activation
Lab abnormalities in liver disease
- increased PT, PTT
- increased D-dimers/FDPs (don’t clear them)
- decreased fibrinogen level
- increased factor VIII level
- decreased platelet count
Treatment for liver disease
- fresh frozen plasma but don’t just treat numbers
Disseminated Intravascular Coagulation (DIC)
- intravascular thrombin formation
- deposition of fibrin in microvasculature
- inhibitors consumed (AT, protein C/S) but fail to control process
- fibrinolysis initiated, fails to remove all the fibrin
- platelet consumption
Signs of DIC
- schistocytes due to thrombosis and vascular occlusion
- increased bleeding due to platelet consumption
Causes of DIC
- sepsis, trauma, cancer (AML)
- obstetrical complications
- vascular disorders
- toxins: SNAKE VENOM, drugs
Lab abnormalities in DIC
- increased PT, PTT
- decreased fibrinogen
- increased D-dimer/FDPs
- decreased platelet count
- fragmented RBCs in blood smear
Treatment of DIC
- treat UNDERLYING disorder
- blood product replacement in patients who are bleeding
Factors requiring vitamin K
- II, VII, IX, X
- protein C & S
Vitamin K deficiency
- hemorrhagic disease of newborn (HDN): prevented by giving vitamin K at birth
- warfarin (coumadin)
- oral antibiotic therapy: decreased gut flora
- poor absorption of vitamin K: biliary tract obstruction, bowel disease
Acquired coagulation abnormalities
- post Op state, bed rest, pregnancy, oral contraceptives, myeloproliferative disorders, cancer, antiphospholipid antibody syndrome (lupus anticoagulant)
Antiphospholipid antibody syndrome
- most common cause of acquired thrombophilia
- development of antibodies against plasma proteins w/ affinity for anionic phospholipids: most commonly Beta2-glycoprotein 1
Antiphospholipid antibody syndrome: clinical findings
- venous/arterial thrombosis
- recurrent fetal loss
- thrombocytopenia
Lupus anticoagulant
- antibody that prolongs phospholipid dependent coagulation tests (PTT)
- may occur in presence OR absence of SLE
- INCREASED risk of clotting even with increased PTT
Factor V Leiden
- mutation in factor V: unable to be cleaved by activated protein C
- prevalence: 3-7% in caucasians
- heterozygous state: only a mild risk factor
Inherited thrombophilias
- prothrombin gene mutation: increased prothrombin
- protein C or S deficiency
- anithrombin deficiency
- hyperhomocyteinemia
- dysfibrinogenemia
Clinical features of thrombophilic patient
- FAMILY HISTORY of thrombosis
- thrombosis at young age
- idiopathic thrombosis
- thrombosis in an unusual site
Morphology of thrombi
- arterial thrombi: platelets & fibrin (WHITE thrombus)
- venous thrombi: cellular elements & thrombin (RED thrombus)
- mural thrombus: attached to wall (LINES OF ZAHN imply thrombus at site of blood flow)
Fates of thrombus
- propagation: extension leading to vessel obstruction
- embolization: travel to other sites
- dissolution: removed by fibrinolysis
- organization: ingrowth of endothelial cells, smooth muscle fibroblasts, vascular flow may be re-established
Clotting cascade pathways
- intrinsic: factors VIII, IX, XI, XII
- extrinsic: factor VII
- common: factor X & II (thrombin)
