MOD4 Disorders of Hemostasis //

vascular and extravascular disorders

disorder of the blood vessels

defect in structure/function of vascular endothelium/subendothelium

can be acquired or inherited

characterized by petechiae, mucosal bleeding, easy bruising

vascular and extravascular disorder lab findings

bleeding time — prolonged

closure time (plt f’n) — prolonged

capillary fragility test — positive

plt count — normal

PT — normal

APTT — normal

acquired vascular disorders

• senile purpura — bruising in elderly due to atrophy and degeneration of subendothelial connective tissue (loss of support)

• simple easy bruising — women of reproductive age, accompanied by thrombocytopenia

• secondary vascular purpuras — endothelial damage

inherited vascular and extravascular disorders examples

• hereditary hemorrhagic telangiectasia HHT

• ehlers-hanlos syndromes

• marfan syndrome

• osteogenesis imperfecta

• homocystinuria

• pseudo xanthoma elasticum

hereditary hemorrhagic telangiectasia HHT

inherited disorder — autosomal dominant defect

affects subendothelial collagen

dilations of capillaries

commonly have arteriovenous fistulae → abnormal connection btwn vein and artery

ehlers-danlos syndromes

inherited

loss of elasticity in the epidermis/subepidermal tissues

abnormal collagen

joint hypermobility

marfan syndrom

defect in chromosome 15

results in abnormal fibrillin in connective tissue

long legs/arms/torso, flexible joints, flat feet

prone to aortic prolapse

osteogenesis imperfecta

brittle bone disease

genetic disorder of defective collagen formation

bones break easily

homocystinuria

inherited disorder

metabolism of aa methionine

tight joints

pseudo xanthoma elasticum

inherited disorder of elastin

elastic tissue (skin, vessels, retina) mineralizes — esp with calcium

causes narrowing of vessels

quantitative disorders of platelets

abnormal numbers of plts in circulation

thrombocytopenia — decreased plts

thrombocytosis — increased plts

thrombocytopenia

most single cause of abnormal bleeding

decrease in plt count below normal values — count drops below 120 = noticeable bruising, below 20 ×10^9/L before severe bleeding

thrombocytopenia lab results

plt count — decreased

bleeding time — prolonged

closure time — prolonged

clot retraction — poor

what causes thrombocytopenia

• decreased/ineffective production of plts

• increased destruction/utilization of plts

• abnormal distribution of plts

decreased/ineffective production of plts causing thrombocytopenia

most common cause of low plt counts

due to marrow hypoplasia or ineffective thrombopoiesis

marrow hypoplasia

abnormal bone marrow → decreased blood cell production

low plt count

decreased megakaryocytes in bone marrow

very few, if any, megathrombocytes in blood smear

ineffective megakaryopoiesis

megakaryocytes fail to survive/normally release plts

low plt count

normal looking marrow → normal numbers

thrombotic thrombocytopenic purpura TTP

deficiency of metalloprotease enzyme ADAMTS-13

breaks up ultra-large vWF multimers (v sticky) to smaller, less adhesive multimers

without ADAMTS-13, multimers are hyperadhesive and plts will adhere when they shouldnt → clots

causes thombocytopenia

hemolytic uremic syndrome HUS

abnormal premature destriction of RBCs

damaged RBCs clog the filtering system in kidneys

E.coli and Shigella → produce toxins that enter BS, attach to endothelial cells in renal capillaries → damage, release of ULvWF multimers → thrombi production in renal vascular system

causes thrombocytopenia

immune thrombocytopenic purpura ITP

platelet antibody sensitizes plts → premature removal by macrophages in the spleen

ab development usually secondary to viral infc or drugs

inc megakaryocytes in marrow

plt antibody in serum

plt count 10-50 ×10^9/L

increased destruction/utilization of plts causing thrombocytopenia

• excessive consumption of plts

• plt antibodies

• transfusions

how transfusions can cause thrombocytopenia

• dilution with plt poor donor blood — rare bcs whole blood gets split into components

• donor plts may be sensitized to plt antibody in patient from prior transfusion

• plts may be lost in extravascular circulation

abnormal distribution of plts causing thrombocytopenia

increased splenic pooling of plts

spleen gets bigger → plts stored, not in circulation

thrombocytosis

an increase in the number of plts in circulation

count exceeds 400 × 10^9/L

qualitative/functional defects in plts causing thrombocytosis

• disorders of plt secretion/release reactions

  • storage pool diseases → deficiencies of dense/alpha granules

  • primary secretion defects

• thrombasthenia (glanzmann disease)

• bernard-soulier syndrome BSS (giant plt syndrome)

storage pool diseases (granule defects)

secondary aggregation disorder

deficiency of dense/alpha granules

dense — intracellular storage for ADP, ATP, Ca, serotonin

alpha — storage for proteins produced by megakaryocyte or in plasma → taken up by plts and transported for storage

grey platelet syndrome

deficiency of alpha granules

agranular appearance of plts with Wright stain

reduced activity of plt factor 3 → defect in aggregation

primary secretion defects (enzyme pathway defect)

granules are normal, but the release reaction isnt working due to deficiencies of enzymes and secondary messengers

thrombasthenia/glanzmann disease

inherited autosomal recessive failure of primary aggregation

reduced amounts of membrane glycoprotein complex GP IIb/IIIa

fibrinogen cant bind to platelet membrane

prolonged bleeding time

defective clot retraction

plt aggregation only normal with ristocetin

bernard-soulier syndrome BSS

giant platelet syndrome

inherited autosomal recessive failure of plt adhesion

reduced amounts of membrane glycoprotein Ib/IX

vWF cant bind to platelet membrane

very large megathrombocytes

increased number of dense granules

prolonged bleeding time

which bleeding disorders cant aggregate with abx ristocetin

bernard-soulier syndrome BSS and von Willebrand disease

BSS → lack of GPIb

VWD → lack of vWF

von willebrand disease VWD

inherited autosomal defect of chromosome 12

reduced synthesis of normal vWF by endothelial cells and megakaryocytes

disorder of plt adhesion → most common bleeding disorder

may also have deficiency of factor 8:C

treatment for VWD

infusion of factor 8 concentrate

desmopressin → nasal injection, causes release of vWF from endothelial cells

testing for VWD

• platelet agglutination test with ristocetin — measures ristocetin-induced agglutination of normal platelets by pts plasma

• platelet aggregation test with ristocetin — measures ristocetin-induced aggregation of pts plts by pts plasma

• VWF antigen

• FVIII:C activity

• VWF multimeric analysis

• bleeding time

what is ristocetin used for

induces plt aggregation in normal plt-rich plasma, but not in pts w VWD and BSS

type 1 VWD

in plasma: partial quantitative deficiency of VWF multimers, distribution of multimers is normal

in plts: normal distribution of multimers, variable conc

most common type

type 2 VWD

qualitative deficiencies of vWF

4 subtypes: 2A, 2B, 2M, 2N

normal numbers, multimers structurally abnormal/absent

type 3 VWD

severe quantitative deficiency of vWF

all multimers decreased or absent in plasma and platelets

acquired/secondary defects

much more common than inherited defects

plt function disordered (usually temporarily) secondary to disease or drug action

most common implicated drug → acetylsalicylic acid/ASA/aspirin: causes decreased plt aggregation

what drug inhibits plt aggregation

acetylsalicylic acid/aspirin

inhibits thromboxane A2 synthesis

cause of coagulation disorders

• failure of synthesis

• production of abnormal molecules

• excessive destruction or consumption of coag factors

• inactivation of coag factors

deficiencies of which factors will produce proportional bleeding to the deficiency

9, 8, 10, 5, 2, 1

severe factor deficiencies

less than 1% of normal level of coagulation factor in the plasma

severe bleeding symptoms

spontaneous hemorrhages from mucous membranes and into joints/muscles

moderate factor deficiency

1-5% of normal levels

moderate symptoms

occasional spontaneous hemorrhages, severe bleeding after minor injury

mild factor deficiency

5-25% of normal levels

mild symptoms

some bleeding after mild trauma, severe bleeding after surgery

which deficiencies would result in a prolonged APTT but no clinical bleeding

factors 12, HMWK, PK

deficiencies in factor 11 and 7 symptoms

disproportionately mild bleeding in patient

deficiency of factor 13 symptoms

disproportionately severe but delayed bleeding

hemophilia A / classic hemophilia

2nd most inherited coag disorder, most common hemophilia

X-linked recessive trait

deficiency or dysfunction of factor 8:C

proportional bleeding to the deficiency of factor

normal PT, abnormal PTT

factor VIII:C

antihemophilia factor

functions as clotting factor/coagulant of FVIII:vWF complex (only 1-2% of the complex)

rest of complex → plt adhesion and stabilization

therapy of hemophilia A

goal: raise pt factor VIII:C to aboce 20% of normal

infusion of FVIII concentrate

desmopressin DDVAP → drug that induces VIII release

pts w VIII ab → bypass FVIII rxn using pre-activated factor X

hemophilia A complications

development of immune VIII antibodies against transfused VIII

development of liver disease bcs of many blood product infusions → exposure to hep B or hep C

hemophilia B/christmas disease

inherited deficiency of coag factor 9

sex linked recessive → Xq27

normal PT, prolonged PTT

treatment of hemophilia B

prothrombin group concentration → F 2, 7, 9, 10, protein C and S

factor 9 concentrate → F 9, 10, 7, 2

stored plasma → 9 is stable in vitro

choice of tx dependent on deficiency

what disorder type would a decreased plt count possibly indicate

hemocytopenias

acquired coagulation deficiencies

much more common

usually occurs in groups → more than one factor decreased

circulating (abnormal) anticoags and antifactors

• specific coagulation factor abs — F8 abs most common

• nonspecific inhibitors of hemostasis — group of antiphospholipid antibodies

  • lupus anticoagulant LA

  • anticardiolipin antibody ACA

lupus anticoagulant LA

antibody that binds to phospholipids and proteins associated with cell membrane, interferes with interactions btwn membrane and clotting factors

cause of venous thrombosis

acts as anticoag in vitro (lab) → prolonged PTT

acts as coagulant (will clot) in vivo (body) → activates plts

anticardiolipin antibody ACA

antibody directed against cardiolipin — component of inner mitochondrial membrane

cause of arterial thrombosis

how do nonspecific inhibitors of hemostasis work — production of thrombosis

reactivity of LA and ACA with plt phospholipids → increased plt adhesiveness

binding of abs to endothelial phospholipids → inhibition of prostacyclin production and release

causes plts to adhere to endothelium → aggregation, vascular obstruction, thrombosis

APTT mixing studies

mix normal plasma and patient plasma

reassess clotting

what if the APTT mixing study remains abnormal

indicates that a clotting inhibitor or antibody is present

reacts with the normal plasma → clots

what if the APTT mixing study is corrected to normal

indicates clotting factor deficiency → normal plasma contains the missing factors

APTT so factors 12, 11, 9, 8

vitamin K deficiency

decreased production of normal vit K dependent coag factors → prothrombin grp factors 2 7 9 10 protein C and S

need the vK to activate into functional factors → bind to Ca → bind to PF3 → coag

prolonged PT and APTT

decreased factor assays

coumadin and vit K

impairs regeneration of active vK

dec activity of vK dependent factors

vitK in newborn infants

lower than in adults, dec further during first few days

lack of storage

absence of intestinal bacteria producing

lack in breast milk

immaturity of liver cells

hemorrhagic disease of the newborn

premature infants with lower liver function

develops severe deficiency of one of prothrombin grp factors

abnormal bleeding

tx: injection of vit K

liver disease

results in reduction in coag factors produced by hepatic cells

• obstructive jaundice — obstruction reduces delivery of bile salts → dec absorption of vK

• severe hepatitis — damaged liver cells dont produce normal quantities of coag factors → 5 and 1

disseminated intravascular coagulation DIC

widespread intravascular coagulation in small vessels

consumption and destruction of coag factors to point of deficiency, thrombocytopenia, abnormal bleeding