Introduction to thrombosis: Proficient and cost-effective approaches to thrombosis

Definition of etiology 

Most instances of arterial and venous thrombosis are unexplained (unassociated with surgery, trauma, cardiac emboli, and so on). Many instances of first-event thrombosis are expensive with respect to cost of care. National average costs for DVT and PE per episode (admission) are presented in Table 2 [9]. Review of these per episode costs of care can facilitate cost savings per patient for each primary or recurrent episode, which can often be prevented.

Table 2. Cost and LOS per admission

	Disease	Average cost ($)	Average losa(d)
	Deep vein thrombosis	9,337	6.3
	Pulmonary embolus	12,795	7.42

a los, length of stay (in hospital).

Current standards of care require that patients with unexplained thrombosis be evaluated thoroughly for hereditary and acquired thrombophilic disorders. The reasons for this are obvious not only for morbidity and mortality but also for cost containment. The cost of an evaluation is minimal compared with the cost of another event or death. The clinician must always recall that up to 58% of patients with unexplained thrombotic events in the face of a seemingly explainable clinical setting (surgery, trauma, oral contraceptives, hormone replacement therapy) do, in fact, have thrombophilic disorders that were simply unmasked by the clinical scenario.

Common and rare blood coagulation protein/platelet defects leading to thrombosis are:

In viewing this list, it must be remembered that most instances of thrombosis are without a clinically known etiology, but often a clinical event associated with thrombosis simply unmasks an underlying blood coagulation protein/platelet defect already harbored by the patient.

Cost containment 

It is of major importance to identify patients with these defects because that will allow the administration of appropriate secondary antithrombotic therapy to decrease the risk for recurrence, the determination of length of time the patient must remain on therapy for secondary prevention, and the testing of family members of patients with hereditary blood coagulation protein or platelet defects (approximately 50% of all coagulation and platelet defects mentioned above), thus facilitating primary prevention in appropriate relatives. The prevalence, as far as is known at present, of coagulation protein/platelet defects in common thrombotic disorders is shown in Table 3. These numbers will likely increase with additional prevalence studies and discoveries of new defects [3], [4], [10].

Table 3. Prevalence of coagulation protein/platelet defects associated with thrombosis in common disorders

	Defect	DVT/PE, %	CVT, %	TIA, %	CAT, %	RVT, %
	Antiphospholipid syndrome	29	65	28.5	18	60
	APC resistance (FV Leiden)	18	3	14	?	7
	Sticky platelet syndrome	14	19	30	18	13
	Prothrombin 20210A	7	7	?	6	?
	Protein S deficiency	6	?	?	7	?
	Protein C deficiency	5.5	?	?	12	?
	Antithrombin deficiency	4	3	?	5	?
	TPA deficiency	?	1	11	16	13
	PAI-1 elevation	?	—	?	11	7
	Plasminogen deficiency	2	?	?	?	?
	Dysfibrinogenemia	?	?	?	?	?
	MTHFR mutations	?	?	?	?	?
	Homocysteinemia	?	?	?	?	?
	Lipoprotein (a)	?	?	?	?	?

Aside from death, significant illnesses occur as a result of arterial or venous thrombotic events, including, but not limited to, paralysis (nonfatal thrombotic stroke), cardiac disability (repeated coronary events), loss of vision (retinal vascular thrombosis), recurrent miscarriage syndrome (placental vascular thrombosis), stasis ulcers, and other manifestations of post-phlebitic syndrome (recurrent DVT). It must be remembered and emphasized that a diagnosis of thrombosis is similar to and as generic as a diagnosis of anemia. One must, in all instances—as in anemia—ask the vital question: What is the etiology of the thrombosis? Like anemia, the specific and appropriate therapy is highly dependent on defining the etiology. Thrombosis, be it arterial or venous, can no longer be viewed as a generic diagnosis. Approaching thrombosis in this manner probably accounts for not only many treatment failures but also for often confusing and conflicting results of clinical trials. Failure to make a specific diagnosis accounts for enhanced morbidity and mortality and exorbitant, unnecessary medical costs for recurrent episodes. Most clinicians and investigators approaching thrombosis as a generic diagnosis fail to note that a heterogeneous population is likely to be present and that outcomes will depend on designing therapy specific for a given etiology. For example, it is senseless to treat a patient with thrombosis and sticky platelet syndrome with heparin or warfarin when the patient needs only aspirin [11], [12]. Neither would it make sense to treat a patient with antiphospholipid syndrome and thrombosis with aspirin (no response) or warfarin (65% failure rate) [4], [13] when the patient will respond most ideally to low-molecular–weight heparin (LMWH) or unfractionated heparin (UFH) [4], [13], [14]. Defining the defect and instituting appropriate therapy will save a minimum of $2.9 million per 1000 patients with DVT [3], [15]. The cost of defining the common blood coagulation protein defects in these patients is $100 to $1500 per patient [3], [15]. Thus, a cost of $1100.00 × 1000 DVT patients ($1.1 million) will save a minimum of $2.9 million [2], [16], [17]. A cost of $1100 per 100 CVT patients ($110,000) will save a minimum of $350,000 [3], [15], [18], [19]. This does not account for additional savings such as rehabilitation, long-term care, long-term wound care for stasis ulcers/infection, and so on; thus, the savings in morbidity is extraordinary and priceless.

Deep vein thrombosis 

The incidence of DVT in the United States is approximately 159 per 100,000, or approximately 450,000 cases per year [5], [6]. A definable etiology can be found in 80% to 90% of these patients; this allows effective therapy to be delivered and allows for the other advantages of defining the blood coagulation protein or platelet defects, mentioned above, to be instituted. For example, approximately 28% of these patients will have antiphospholipid syndrome, and approximately 65% of oral anticoagulant treatment will fail (thrombosis will recur) [4]. Each of these failures will result in readmission of the patient at a cost of approximately $6000 to $7000, with an average length of stay (LOS) in the United States of approximately 6 to 7 days. In addition, approximately 30% to 50% of these patients will have coagulation protein or platelet defects that are congenital. Thus, family members should be assessed and spared a first event by the institution of appropriate therapy at appropriate times, depending on clinical status (oral contraceptives, hormone replacement therapy, impending surgery, trauma) [3]. Obviously, antithrombotic therapy for the patient should be long term, not simply for 6 weeks to 3 months [18]. The cost of an evaluation for common blood coagulation protein/platelet defects is approximately $1100 to $1500. This is minimal when considering that approximately 28% of patients with DVT/PE have antiphospholipid syndrome and that warfarin or antiplatelet therapy fails 65% of patients but that subcutaneous porcine heparin every 12 hours or subcutaneous LMWH every 24 hours fails only 1% of patients. Approximately 14% of DVT/PE patients have sticky platelet syndrome (SPS), warfarin or heparin/LMW heparin therapy will fail almost all of them, but 81 mg/day aspirin will fail less than 1% of them [4], [16]. Activated protein C resistance (factor V Leiden and other factor V mutations), protein C, protein S, antithrombin deficiency, and prothrombin Gly20210Arg mutation are probably best treated with warfarin, unless the patient has a recurrence. In that case, LMWH is preferred. The rarer defects mentioned in Table 3 are probably best treated with warfarin, though additional studies are needed to define the ideal therapy for many patients. Thus, the importance of effective therapy and the cost of effective therapy are negligible compared with the cost of recurrence, morbidity of recurrence, and impact on quality of life. In addition, if patients are simply offered generic therapy, usually in the form of initial inpatient heparin for 5 to 7 days followed by outpatient warfarin for 6 weeks to 6 months, those with blood coagulation protein/platelet defects refractory to warfarin will have recurrences of thrombosis, and 40% of them will then acquire chronic venous insufficiency (post-phlebitic syndrome). The sequelae of post-phlebitic syndrome consists of a life-long experience of recurrent DVT/PE requiring many hospital admissions and the development of stasis ulcers requiring vigorous wound care and long-term expensive antibiotic and other supportive therapy [17], [20]. The costs of allowing unnecessary recurrence and development of chronic venous insufficiency are exorbitant beyond calculation; the morbidity and potential mortality are also devastating. Cost containment for appropriately defining the precise etiology (blood coagulation protein/platelet defect) in DVT/PE patients is summarized in Table 4. Costs of heparin, LMWH, warfarin, and ASA therapy are summarized in Table 5 [15], [16], [21].

Table 4. Cost reduction by prevention of recurrence

	Deep vein thrombosis	Cost of acute care, $
	100 events/y	933,700
	Assume 70% are candidates for evaluation	636,590
	Assume 80% have treatable findings	522,872
	Cost of evaluation	(75,950)
	Savings per 100 DVT patients	446,922

Includes use of appropriate secondary therapy.

Table 5. Cost of common antithrombotic drugs

	Drug	Cost, $
	Unfractionated heparina	210.00
	Low-molecular–weight heparinb	209.60
	Warfarin (Coumadin, 7.5 mg/d)c	28.05
	Aspirin (81 mg)	0.45

Costs are for 5 days of therapy.

a Includes daily PTT at 1992 cost ($35.00) and intravenous or dose-adjusted therapy. b Assumes 70-kg patient (dalteparin). c Assumes one prothrombin time (INR).

Current standards of care require that patients with unexplained thrombosis be evaluated thoroughly for hereditary and acquired thrombophilic disorders. The reasons for this are obvious, not only for morbidity and mortality but also for cost containment. The cost of an evaluation is minimal compared with the cost of another event or death. Regarding a so-called unexplained thrombotic event, the clinician must always recall that up to 58% of patients with thrombotic events, in the face of a seemingly explainable clinical setting (surgery, trauma, oral contraceptives, hormone replacement therapy), have a thrombophilic disorder that was simply unmasked by the clinical scenario.