hypercoagulable

states
approach to the paLent with hypercoagulable state
when to consider: thrombosis at early age. mulLple thrombosis. unusual site. family history. :: venous or arterial? venous = classic hypercoag states. arterial= not usually assoc. with hypercoag states [tend to be assoc. with athero or embolism] :: where is it? unusual places = cerebral vein, mesenteric vein [PNH, myeloproliferaLve syndromes], upper extremity [NOT assoc. w/ hypercoag states] :: how old is the pt? kids = unusual to have clots. young adults= think inherited [50% occur w/ provocaLon]. older folks- acquired. :: any risk factors? :: family hx? incomplete penetrance. get detailed hx [aunts, uncles, cousins]

VENOUS hypercoagulable states [classic]

venous thrombosis. tend to occur b/c Virchow's triad: abnl vessels, abnl blood, venous stasis]. venous clots are brin rich w/ RBCs= RED. tend to be large. most common in deep veins of legs [can occur anywhere]. obstrucLon= pain and swelling. feared complicaLon= thromboembolism= acute obstrucLon of pulm artery/death. +classics: anLthrombin, ProC, ProS. not as common 1-5% hypercoag states. RR of thrombosis= 10. only venous + LOF or GOF. LOF= loss of anLcoag. less common but more severe [anLthrombin, proC and proS. GOF= more thrombogenic stu. very common, but less severe [factor V and prothrombin] venous hypercoagulable states :: inherited defects. majority= defects in protein C system. common- 10% of people. the big ve: + anAthrombin. nl= binds to/ inacLvates acLvated cloYng factors [thrombin or Xa]. deciency = acLvated factors circulate. 1/5,000 people. AD. tested by measuring anLthrombin acLvity. + protein C. s erine protease- breaks down acLvated V and VIII. deciency: persistence of Va and Vllla= conLnued coagulaLon. 1/2,000 peeps. AD. rare homozygous= thromboses soon a`er birth. measure protein C acLvity. levels go down with warfarin. + protein S. essenLal cofactor for protein C. either free or plasma-protein bound. only free can prevent thrombosis. pt can either be decient in total or free [this form is far more common]. 1/2,000. AD. measure protein S acLvity. levels decreased by warfarin. + factor V Leiden. acLvated C and S work by destroying acLvated V and VIII. abnl factor V [ARG506GLN] is a point mutaLon in the C cleavage site. VERY COMMON in some populaLons. up to 50% of pts with hypercoag states have it. 20% of those w/ rst Lme DVTs and 5-10% of normal populaLon. as many as 1/2000 are homozygous. and is a major risk factor for venous thrombosis esp in women taking OCPs [increases risk 30X] test by acLvity assay [APC resistance test] cheaper than PCR of mutaLon. can get DVT, cerebral vein thromb. NOT assoc. with MI or strokes. + prothrombin gene mutaAon. mutaLon in 3 UTR of prothrombin gene. appears to raise the level of prothrombin. risk of cerebral vein T= 3-10X, DVT.= 2-3X. dramaLc elevaLon w/ OCPs. NO risk of MI. test by PCR.

ARTERIAL hypercoagulable states

arterial thrombosis. tend to be small [mm]. o`en occur over ruptured atheromatous plaque. arteries may be plugged by emboli. arterial thrombi are white from platelets. more common in cerebral vasculature + coronary arteries. happen from years of vascular abuse by smoking, high cholesterol= atheroscleroLc plaque rupture and acLvaLon of coag and platelets. :: geneAcs. anything that = increased plasma cholesterol, or rare collagen and other conn. Lssue defects. [lupus inhibitors or high Lter ACLA. :: acquired. biggest and most preventable= smoking. :: embolism. clots from heart. + cardiomyopathies. large dilated ventricles= enlarged thrombiembolize.1/4-1/2 strokes happen this way. + A b. if untreated=strokes ~5%/year. one-2 million people. use of anLthromboLc tx decreases this a lot. leading cause of preventable stroke.

VENOUS + ARTERIAL hypercoagulable states [acquired]

clues. urry of thrombosis. older age of onset, refractory to warfarin, both venous and arterial thrombosis. common. eAology. producLon of procoagulants [cancer: neoplasLc cell expresses Lssue factor, IBS: endothelial and monocyte expression of TF] and/or reducLon in natural coagulants [ nephroLc syndrome: anLcoag like protein S excreted along with other proteins in the urine, inammaLon: increased concentraLon of protein that binds proS= lower the free levels. o`en from complicaLon of underlying disorder and can oer clues to presence of disorder. :: cancer. thrombosis can be presenLng sign of CA. 10-20% of older pts w/ DVT= CA. other signs increase concern of CA: warfarin refractory thrombosis, idiopathic bilateral DVT, art+venous thrombosis. pts w/ DVT have 7-20% of cancer in next 2 years- risk highest in rst 6 mo. [pancreaLc, lung, brain, prostate, adenocarcinoma]. e Aology: tumor expressing TF, inamm. cytokines, changes in natural anLcoags, immobilizaLon, TX[ endo damage]. tamoxifen= increased risk of thrombosis. evaluaAon: rouLne CA screening at Lme of DVT dx. suspicious pts- CT scan abd and chest. vast majority have metastaLc dz. TX:some evidence that heparin beler than warfarin but $$ but give warfarin rst unless GI, lung, or brain tumors, or if they have broken through warfarin or are on aggressive therapy for cancer. :: nephroAc syndrome and other renal dz. renal vein and other thrombosis + higher incidence of thrombosis. big problem if get gra` thrombi where dialysis hooks up. pathogenesis: loss of anLcoag [anLthrombin and protein S] + inamm. homocysteine levels may also play role. :: IBD. thrombosis very common [up to 33% at autopsy]. DVT most common. visceral vein and aorLc occlusions also. pathogenesis: inammatory cytokines, low protein S [increased levels of C4B-binding protein/acute phase reactant] DX: by history of iBD. TX: anLcoag [but increases bleeding], surgery. :: estrogen. key principles: estrogen in any dose= thrombosis, estrogen-like and estrogen opposers= thrombosis. dose dependent. age increases risk + past predicts the future. pathogenesis: decreased protein S, increased VIII, other/unknown. OCPs: 12 million women in US- most common med in young women. even with lower estrogen-containing pills: risk remains. risk= 3X [from 1/10,000 to 3/10,000], higher with 1st and 3rd generaLon [because of high estrogen and high progesterone]. OCP + hypercoag: dramaLc increases- RR=10-99!!. highest in OCPs w/ desogestrel and gestodene. absolute risk = 28-50/10,000. should women be screened for hypercoag states? no. need to deny contracepLon to >60 women to prevent one DVT. patches and rings: patches have same to higher risk as pills. rings= unknown, probably similar. HRT: RR=2 w/out hyper coag. WITH hypercoag= RR 6.7-17. increased also because of age. estrogen-like drugs: all that interfere w/ estrogen= prothromboLc. tamoxifen= DVT 3X. raloxifene= 2X, aromatase inhibs= slight increase. pregnancy: high estrogens, venous stasis, bed rest, risk rises w/ age. most women w/ DVT during pregnancy have hypercoag state [preg + state= RR of 57]. placental ischemia= decreased fetal growth, fetal death, preeclampsia. frequent miscarriage= look for hypercoag states esp if a`er 10 weeks.

therapy for venous and arterial hypercoagulaLon

duraAon. 6 months: hypercoag state + provoked DVT or provoked proximal DVT. 3 months: spontaneous upper extremity thrombosis. 6 weeks: calf vein DVT or provoked upper extremity. INDEFINATE: with even just one DVT, if pt has CA, APLA [anLphospholipid anLbody syndrome], MPS, more than one DVT, unusual site, idiopathic PE. big idiopathic DVT. gure out why. to have explanaLon, prescribe specic therapy, family screening to prevent others rst thrombosis. venous. oral anLcoag [warfarin] for at least 6 mo. biggest and most predicLve factor for risk of recurrence is whether thrombosis was PROVOKED [surgery, trauma, estrogens, etc...], or IDIOPATHIC [have much higher rate of recurrence + should be anLcoag indenitely. arterial. tx atherosclerosis. risk factor control- diet and smoking. treated w/ oral anLcoag also.

hypercoagulable states