Dr Suman Kumar Pramanik
Classified Specialist (Medicine) & Clinical Hematologist
Department of Clinical Hematology and Bone Marrow Transplantation
Army Hospital (Research and Referral)
The most common presentations of venous thromboembolism (VTE) are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism. The causes of venous thrombosis can be divided into two groups - hereditary and acquired, and are often multiple in a given patient. VTE mainly includes DVT and pulmonary embolism (PE) and is the third most common vascular disorder after coronary artery disease and stroke.
Exposure to high altitude (HA), either during long-haul air flights or ascent to HA (either during mountaineering expeditions or as a part of military duties) or within sports arena exhibits a direct and proportionate relation to the frequency of occurrence of thromboembolic complications.
The exact prevalence of VTE in HA areas and cause-effect relationship between the HA exposure and VTE is not yet well established due to peculiarities, scarcity and relative inaccessibility of this population.
In this discussion, I will try to address these issues, and finally close by giving practical tips on suspicion, early management and prevention of these potentially fatal diseases.
A major theory delineating the pathogenesis of VTE was described in mid nineteenth century by Rudolf Virchow partially and then formulated by different workers over next centuries, to reach its final form, termed “Virchow’s Triad”.
The triad proposes that VTE occurs as a result of:
Alterations in blood flow (ie, stasis).
Vascular endothelial injury.
Alterations in the constituents of blood (ie, inherited or acquired hypercoagulable state).
The following are the suggested factors present in HA regions which predispose to development of VTE.
Prolonged Immobilization: It leads to venous stasis.
Less fluid intake: As a part of extremely cold climate leading to decreased thirst, it leads to increased viscosity.
Following are the proposed (few of them proven) alterations in blood constituents and endothelial dysfunction which are associated with HA:
HA hypoxia: Hypobaric hypoxia has been proposed to be thrombogenic, although there are limited data to establish the exact correlation between the two. As mentioned above, it is a well known cause for HA polycythemia. There has been conflicting reports on association of hypercoagulable state (other than polycythemia) and hypoxia in human studies, but results from cell culture studies have shown that cultured endothelial cells are characterized by enhanced procoagulant activity on exposure to hypoxia. It has also been proposed that, pulmonary and cerebral circulatory micro-thrombi are the precursors for high altitude pulmonary edema and cerebral edema respectively.
HA hypercoagubility: Several studies have demonstrated a state of reversible hypercoagubility on exposure to HA. There is a tendency to higher levels of coagulation factors (factor VIII, fibrinogenplatelet factor 4) and anti-fibrinolytic factors (PAI-1).
Platelet and other hematological factors: There have been conflicting reports on increased platelet counts on exposure to HA. One study had demonstrated significant increase in thrombopoeitin, erythropoeitin and platelet counts and positive correlation between thrombopoeitin levels and platelets, while others have failed to find any association. A recent study has demonstrated increased CAPNS1 dependent calpain activity in rats exposed to hypoxic condition.
Endothelial dysfunction: There are limited experimental evidences which indicate that exposure of cultured human venous endothelial cells to hypoxia may increase their procoagulant activity and inhibit fibrinolysis. However, understanding of exact mechanism for endothelial dysfunction in HA is lacking.
Genetic factors: There are limited data to link the role of genetic background to the development of thrombosis at HA. But, inherited thrombophilic state are proposed to be additional cause for hypercoagubility in people staying at HA.
There have been only a few studies, mostly from Indian Armed Forces which have indirectly found some evidence of positive association between HA and VTE. These studies are mostly hospital based and are not adequately designed to eliminate effects of confounders and are limited by patient numbers.
In the hospital based cohort study done by Anand AC, et al from CH (WC), out of 20257 patients admitted over a period of 2 years, 1692 were from HA region. The cumulative incidence among patients who were from HA and normal altitude was 27.2 per 1000 admissions and 0.9 per 1000 admissions respectively (OR: 30.49, 95% CI: 17.06 - 51.67). Many of the confounding factors were not adequately matched in the above study. Other than this study, there is no other epidemiological study which tries to answer the above association.
It is of paramount importance that the medical officer at HA posts, staying with the troops at HA areas are aware of the common manifestations of different forms of VTE and are able to catch these patients clinically, so that appropriate steps can be taken by them at right time to save lives of patients.
Spectrum of VTE: The common manifestations of VTE include deep venous thrombosis of lower limbs, pulmonary thrombo-embolism (usually results from embolus from proximal lower limb DVT), mesenteric vein and portal vein thrombosis.
Time of onset: Usually VTE in HA areas occur after at least 2 weeks of stay at that altitude. Acute mountain sickness (AMS), pulmonary edema and cerebral edema usually occurs during first 7 - 10 days of induction to HA areas.
Acutely breathless patient in HA: Differential diagnoses for a patient at HA with breathlessness are high altitude pulmonary edema (HAPE), pulmonary thrombo-embolism (PTE), pneumonia and myocardial infarction (MI). A recently inducted patient with features of AMS in first week of induction usually point towards HAPE. Patient with a bit longer stay in HA with lower limb painful swelling (which may not be there in 40% of cases) usually points towards PTE. Associated central chest pain can occur in AMI and massive PTE. Associated fever occurs in pneumonia. Tachycardia is usually present in all the above situation and is indicator of sickness of the patient. Hemoptysis can occur in HAPE, pneumonia and PTE. Pink frothy sputum occurs in HAPE, or cardiogenic pulmonary edema. Scanty hemoptysis with pleuritic chest pain occurs in peripheral PTE (with pulmonary infarction) and in pneumonia. Chest auscultation can be revealing in this situation. Extensive crackles are heard in HAPE, cardiogenic pulmonary edema and rarely in pulmonary edema induced by PTE. In PTE, lung fields are usually clear or they can show localized crackles, pleural rub or evidence of pleural effusion.
Acute onset altered sensorium in HA: The main differential diagnoses in a patient with acute onset altered sensorium is high altitude cerebral edema (HACE) or CVT. There seems to be pathophysiological similarity between these two disease, both are due to venous or micro vascular thrombosis. It is extremely difficult to differentiate between these two diseases clinically. Both of these will lead to headache, may be seizures, altered sensorium and features of raised intra-cerebral pressure (high blood pressure and bradycardia). Focal neurological deficits can be seen in both of the diseases, more in CVT. Only focal neurological deficit without altered sensorium usually points towards ischemic stroke.
Features of DVT lower limbs: Forty percent of acute lower limb DVT are asymptomatic. Usual presentation is unilateral, painful leg swelling occurring over a few days.
Features of splanchnic vein thrombosis: Mesenteric vein thrombosis should be suspected in any patient with pain abdomen lasting for more than 1 day duration, not responding to antacids and analgesics, especially if associated with tachycardia, features of peritonitis (abdominal guarding, absent peristaltic sounds and vomiting), bloody stools, and evidence of shock. Portal vein thrombosis is usually asymptomatic or associated with pain abdomen. Hepatic vein thrombosis (Budd Chiari Syndrome) may present as acute hepatic failure (jaundice, liver failure, painful hepatomegaly, may be encephalopathy) and ascitis or may be asymptomatic.
Unfortunately, MOs situated at the site of occurrence of these illnesses are not equipped with even the basic diagnostic facilities. It is imperative that the Mos situated at far flung areas should have very high degree of suspicion of VTE, if any patient presents with one of the above symptoms. Moreover, timely evacuation of patients are also problematic many a times due to unfavorable climatic conditions, enemy action or unavailability of appropriate transport mechanism. So, MOs should also be equipped for providing initial management of the above diseases, mostly only on clinical suspicion and clinical presentation alone.
As soon as the patient is brought to the attention of medical care-giver, after providing basic resuscitation, the first and foremost step is organizing safe and rapid evacuation of patient to a hospital at normal altitude, usually by air.
Bed rest and strict instruction not to massage involved limb is required for patient with DVT.
Low molecular weight heparin (LMWH) can easily and safely be administered for a few days in patients with suspicion of VTE in HA regions without any laboratory monitoring. Actively bleeding patient or patient who is having active peptic ulcer disease or recent stroke or intra-cranial bleed constitute patient group in which LMWH is a contraindicated. It is a must have medicine at all the HA posts. Usual dose for Inj Enoxaparin is 1 mg/kg SC twice a day for treating VTE.
In hospitals, all efforts should be made to reach a diagnosis by doing ultrasound doppler studies and contrast CT angiography of the target vascular bed. All patients should be started on or continued on anticoagulation with LMWH and then switched over to oral anticoagulation with vitamin K antagonist (warfarin, acenocoumarol, etc) {goal PT(INR) of 2 - 3} after a period of overlap.
Peculiar presentations of PTE: PTE can be a great mimicker. It can easily be confused with acute pneumonia or pulmonary tuberculosis, as it can present with fever, cough, pleuritic chest pain and scanty hemoptysis. It can also present with hemorrhagic pleural effusion. It should be a differential diagnosis in a patient from HA with consolidation or hemoptysis, especially in a patient with recent history or subsequent development of painful swelling of lower limbs (suggestive of DVT).
Indications for systemic thrombolysis: Systemic thrombolysis with streptokinase or with recombinant tissue plasminogen activator is to be carried out in patients with massive PTE (defined as PTE with hypotension or RV dysfunction on echocardiographic studies) and as limb saving measure in patients with iliac vein thrombosis with vascular compromise of lower limb.
Anticoagulation in CVT: Anticoagulation is required in CVT, even with hemorrhagic transformation.
There are no well laid down guidelines for prevention of VTE in HA areas. These group of diseases are potentially fatal and are involved with a great degree of morbidity and associated with long term treatment with anti-coagulation, which are associated with real risk for bleeding.
The logical steps for preventing VTE (especially DVT lower limbs) will be:
Proper screening of people ascending to HA areas with emphasis on history of family members having DVT, prior history of DVT or other thrombotic events. Prior blood count and spleen size estimation should be done to rule out hemolytic anemia, polycythemia vera or other myeloproliferative diseases. Sickle cell disease should be ruled out during screening process.
Smoking, tobacco usage should be stopped on ascending to HA areas.
Adequate hydration should be maintained on ascent to HA areas.
Regular mobilisation of limbs to be done by going on patrolling or by walking around the living sites.
Limb immobilisation should be done and messaging must be avoided at all cost once patient develops DVT, to prevent potentially fatal PTE.